U.S. patent application number 10/337914 was filed with the patent office on 2004-08-12 for 4-dedimethylamino tetracycline compounds.
Invention is credited to Nelson, Mark L., Ohemeng, Kwasi.
Application Number | 20040157806 10/337914 |
Document ID | / |
Family ID | 27541208 |
Filed Date | 2004-08-12 |
United States Patent
Application |
20040157806 |
Kind Code |
A1 |
Nelson, Mark L. ; et
al. |
August 12, 2004 |
4-Dedimethylamino tetracycline compounds
Abstract
The present invention pertains, at least in part, to novel
substituted 4-dedimethylamino tetracycline compounds. These
tetracycline compounds can be used to treat numerous tetracycline
compound-responsive states, such as bacterial infections and
neoplasms, as well as other known applications for minocycline and
tetracycline compounds in general, such as blocking tetracycline
efflux and modulation of gene expression.
Inventors: |
Nelson, Mark L.; (Wellesley,
MA) ; Ohemeng, Kwasi; (Norwood, MA) |
Correspondence
Address: |
LAHIVE & COCKFIELD, LLP.
28 STATE STREET
BOSTON
MA
02109
US
|
Family ID: |
27541208 |
Appl. No.: |
10/337914 |
Filed: |
January 6, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60367049 |
Mar 21, 2002 |
|
|
|
60346930 |
Jan 8, 2002 |
|
|
|
60346929 |
Jan 8, 2002 |
|
|
|
60347065 |
Jan 8, 2002 |
|
|
|
60346956 |
Jan 8, 2002 |
|
|
|
Current U.S.
Class: |
514/152 ;
549/358; 552/204 |
Current CPC
Class: |
A61P 1/12 20180101; A61P
1/16 20180101; C07C 237/26 20130101; C07C 271/58 20130101; C07C
2601/10 20170501; A61P 9/10 20180101; A61P 33/06 20180101; A61P
35/00 20180101; A61P 35/04 20180101; A61P 29/00 20180101; C07D
317/60 20130101; C07C 311/06 20130101; C07C 271/22 20130101; C07C
381/10 20130101; A61P 11/02 20180101; A61P 11/04 20180101; A61P
27/02 20180101; C07F 9/2475 20130101; C07C 333/08 20130101; C07C
2603/46 20170501; A61P 31/04 20180101; C07C 275/54 20130101; A61P
13/02 20180101; C07C 255/41 20130101; A61P 35/02 20180101; C07C
279/18 20130101; A61K 31/65 20130101; A61P 25/00 20180101; C07C
275/42 20130101; C07C 311/08 20130101; A61P 43/00 20180101; A61P
15/02 20180101; C07C 235/70 20130101; A61P 25/14 20180101; C07D
295/185 20130101; A61P 9/00 20180101; A61P 19/10 20180101; A61P
1/02 20180101; C07C 271/54 20130101; A61P 17/02 20180101; C07D
295/155 20130101; A61P 19/02 20180101; C07C 251/48 20130101; A61P
3/10 20180101; A61P 1/04 20180101; A61P 31/10 20180101; C07C
2601/08 20170501; C07C 335/22 20130101; A61P 11/00 20180101; C07F
9/4006 20130101; C07C 2601/16 20170501; A61P 25/28 20180101; A61P
13/10 20180101 |
Class at
Publication: |
514/152 ;
552/204; 549/358 |
International
Class: |
A61K 031/65; C07D
311/78; C07C 237/26 |
Claims
1. A substituted tetracycline compound of Formula I: 1742wherein: X
is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, C.dbd.CR.sup.6'R.sup.6, S,
NR.sup.6, or O; R.sup.2 and R.sup.2' are each independently
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety; R.sup.4 and
R.sup.4' are each independently alkyl, alkenyl, alkynyl, hydroxyl,
halogen, hydrogen, or when taken together the oxygen of a carbonyl
group; R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety; R.sup.5 is hydroxyl, hydrogen,
thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl,
alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
R.sup.6 and R.sup.6' are each independently hydrogen, methylene,
absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; R.sup.7 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, or --(CH.sub.2).sub.0-3NR.sup-
.7cC(.dbd.W')WR.sup.7a; R.sup.9 is hydrogen, nitro, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
arylalkyl, amino, arylalkenyl, arylalkynyl, thionitroso(e.g.,
--N.dbd.S), or --(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a; Z is
CR.sup.9dR.sup.9e, S, NR.sup.9b or O; Z' is O, S, or NR.sup.9f; W
is CR.sup.7dR.sup.7e, S, NR.sup.7b or O; W' is O, NR.sup.7fS;
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.9a,
R.sup.9b, R.sup.9c, R.sup.9d, and R.sup.9e are each independently
hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety; R.sup.8 is
hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and Y' and Y are each independently hydrogen, halogen,
hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts thereof.
2. The tetracycline compound of claim 1, wherein R.sup.4 and
R.sup.4' are hydrogen or the oxygen of a carbonyl group, X is
CR.sup.6R.sup.6'; R.sup.2, R.sup.2', R.sup.6, R.sup.6', R.sup.8,
R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are each hydrogen; and
R.sup.5 is hydroxy or hydrogen.
3. The tetracycline compound of claim 2, wherein R.sup.4, R.sup.4',
and R.sup.5 are each hydrogen.
4. The tetracycline compound of claim 3, wherein R.sup.7 is
aryl.
5. The tetracycline compound of claim 4, wherein R.sup.7 is
substituted or unsubstituted phenyl.
6. The tetracycline compound of claim 4, wherein said aryl group is
substituted or unsubstituted napthyl.
7. The tetracycline compound of claim 4, wherein R.sup.7 is
heteroaryl.
8. The tetracycline compound of claim 3, wherein R.sup.7 is
substituted or unsubstituted alkyl.
9. The tetracycline compound of claim 3, wherein R.sup.7 is
substituted or unsubstituted alkenyl.
10. The tetracycline compound of claim 3, wherein R.sup.7 is
substituted or unsubstituted alkynyl.
11. The tetracycline compound of claim 3, wherein R.sup.7 is
alkylcarbonyl amino.
12. The tetracycline compound of claim 3, wherein R.sup.7 is
carbonyl.
13. The tetracycline compound of claim 3, wherein R.sup.7 is
substituted or unsubstituted imino.
14. The tetracycline compound of claim 3, wherein R.sup.7 is
NR.sup.7c(C.dbd.W')WR.sup.7a.
15. The tetracycline compound of claim 3, wherein R.sup.7 is
sulfonamido.
16. A tetracycline compound of the formula 1743wherein: R.sup.7 is
a fused ring moiety of the formula 1744where Q is C or a
heteroatom; an acylfuranyl group; a tri-, tetra- or penta- halo
substituted phenyl group; an aminomethylphenyl group; an
acylaminomethyl group; an alkylesterphenyl group; an acylphenyl
group; an acylalkynyl group; an acylalkoxyphenyl group; a
methylphenyl group; a dimethylphenyl group; a carboxyphenyl group;
a carboxyalkynyl group; a thiophene group; a halothiophene group;
an alkoxycarbonylphenyl group; an alkoxyphenyl group; an
alkoxyphenylalkynyl group; an alkoxypyridyl group; an
alkylenepyridine group; a cyclopentyl or cyclopentenyl group; a
cyclohexylalkynyl group; a cyclohexenylalkynyl group; a
cyclohexenylhaloalkenyl group; a hydroxycyclohexylalkynyl group; a
phenylalkynyl group; a phenylalkenyl group; an aminoalkynyl group;
a cyclobutylalkenyl group; a pyridylalkynyl group; a pyridylalkenyl
group; a nitrophenylalkynyl group; a nitrophenylalkenyl group; a
cyanoalkynyl group; an alkynyl group; a cyanoalkenyl group; a
cyanophenyl group; a dialkylamidoalkenyl group; a
dialkylamidophenyl group; an aminophenylethyl group; an
aminophenylethynyl group; a haloethenyl group; a halophenylalkynyl
group; or an alkylester-substituted pentenyl group; and
pharmaceutically acceptable salts, esters and prodrugs thereof.
17. A 7,9-substituted tetracycline compound of Formula III:
1745wherein: X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6,
or O; R.sup.2 and R.sup.2' are each independently hydrogen, alkyl,
alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a
prodrug moiety; R.sup.4 and R.sup.4' are each independently alkyl,
alkenyl, alkynyl, hydroxyl, halogen, hydrogen, or when taken
together the oxygen of a carbonyl group; R.sup.2', R.sup.3,
R.sup.10, R.sup.11 and R.sup.12 are each hydrogen or a pro-drug
moiety; R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy; R.sup.6 and R.sup.6' are
each independently hydrogen, methylene, absent, hydroxyl, halogen,
thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R.sup.7
is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl,
arylalkynyl, or --(CH.sub.2).sub.0-3NR.sup- .7cC(.dbd.W')WR.sup.7a;
R.sup.9 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl,
arylalkynyl, thionitroso, or --(CH.sub.2).sub.0-3NR.sup.9cC(-
=Z.dbd.)ZR.sup.9a; Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O; Z' is
O, S, or NR.sup.9f; W is CR.sup.7dR.sup.7e, S, NR.sup.7b or O; W'
is O, NR.sup.7fS; R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e,
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, and R.sup.9e are each
independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; R.sup.8 is
hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and Y' and Y are each independently hydrogen, halogen,
hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts thereof, provided
that R.sup.7 and R.sup.9 are not both unsubstituted phenyl.
18. The tetracycline compound of claim 17, wherein X is
CR.sup.6R.sup.6'; R.sup.2, R.sup.2', R.sup.6, R.sup.6', R.sup.8,
R.sup.10, R.sup.11, and R.sup.12 are each hydrogen; R and R.sup.4'
are each hydrogen or the oxygen of a carbonyl group; and R.sup.5 is
hydroxy or hydrogen.
19. The tetracycline compound of claim 18, wherein R.sup.4 and
R.sup.4' are each hydrogen and R.sup.5 is hydrogen.
20. The tetracycline compound of claim 19, wherein R.sup.7 is
aryl.
21. The tetracycline compound of claim 20, wherein R.sup.7 is
substituted or unsubstituted phenyl.
22. The tetracycline compound of claim 19, wherein R.sup.7 is
substituted or unsubstituted alkyl.
23. The tetracycline compound of claim 19, wherein said R.sup.7 is
acyl.
24. The tetracycline compound of claim 19, wherein R.sup.7 is
substituted or unsubstituted alkynyl.
25. The tetracycline compound of any one of claims 17, 20, 22, 23
or 24, wherein R.sup.9 is substituted or unsubstituted aryl.
26. The tetracycline compound of any one of claims 17, 20, 22, 23
or 24, wherein R.sup.9 is substituted or unsubstituted alkyl.
27. The tetracycline compound of any one of claims 17, 20, 22, 23
or 24, wherein said R.sup.9 is acyl.
28. The tetracycline compound of claim 27, wherein R.sup.9 is
acetyl.
29. The tetracycline compound of any one of claims 17, 20, 22, 23
or 24, wherein R.sup.9 is substituted or unsubstituted alkynyl.
30. A tetracycline compound of formula IV: 1746X is
CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or O; R.sup.2,
R.sup.7' and R.sup.7" are each hydrogen, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,
arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, aryl, hydroxyl, alkoxy halogen, hydrogen, or taken
together to form the oxygen of a carbonyl; R.sup.2', R.sup.3,
R.sup.10, R.sup.11 and R.sup.12 are each hydrogen or a pro-drug
moiety; R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy; R.sup.6 and R.sup.6' are
independently hydrogen, methylene, absent, hydroxyl, halogen,
thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R.sup.7
is NR.sup.7'R.sup.7", alkyl, alkenyl, alkynyl, aryl, hydroxyl,
halogen, or hydrogen; R.sup.9 is nitro, alkyl, alkenyl, alkynyl,
aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl,
amino, arylalkenyl, arylalkynyl, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a; Z is
CR.sup.9dR.sup.9c, S, NR.sup.9b or O; Z' is NR.sup.9f, O or S;
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9d and R.sup.9f are
each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; R.sup.8 is
hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; Y' and Y are each independently hydrogen, halogen,
hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts, esters and
prodrugs thereof.
31. The tetracycline compound of claim 1, wherein R.sup.4 and
R.sup.4' are each hydrogen or the oxygen of a carbonyl group; X is
CR.sup.6R.sup.6'; R.sup.2, R.sup.2', R.sup.5, R.sup.6, R.sup.6',
R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are each
hydrogen; R.sup.7 is NR.sup.7'R.sup.7"; R.sup.7' and R.sup.7" are
each lower alkyl; and R.sup.4 and R.sup.4' are each hydrogen.
32. The tetracycline compound of claim 31, wherein R.sup.9 is
substituted or unsubstituted aryl.
33. The tetracycline compound of claim 31, wherein R.sup.9 is
substituted or unsubstituted alkynyl.
34. The tetracycline compound of claim 31, wherein R.sup.9 is
alkyl.
35. The tetracycline compound of claim 31, wherein R.sup.9 is
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a.
36. The tetracycline compound of claim 31, wherein R.sup.9 is
--N.dbd.S.
37. The tetracycline compound of claim 31, wherein R.sup.9 is
aminoalkyl.
38. The tetracycline compound of claim 37, wherein said aminoalkyl
is alkylaminoalkyl.
39. The tetracycline compound of claim 31, wherein R.sup.9 is
substituted or unsubstituted alkyl amino.
40. A tetracycline compound of the formula: 1747wherein: R.sup.7
and R.sup.7" are each alkyl; and R.sup.9 is a pyridylethynyl group;
an alkenylcarbamate group; a halo group; an alkylacrylate group; a
naphthyl group; a haloacetyl group; an alkyl carbamate group; a
cyclopentyl or cyclopentenyl group; a benzofuranyl group; a
phenylpropiononeamino group; a tosylamino group; a methoxypyridyl
group; an alkeneamino group; an N-t-butyl group; a t-butylamide
group; a hydroxybutylamino group; a hydroxypropylamino group; a
phenyl group; a nitrophenyl group; a nitrophenylalkynyl group; an
aminophenyl group; an alkoxyphenyl group; a halophenyl urea group;
a cyanophenyl group; a carboxyphenyl group; an acylphenyl group; an
alkylphenyl group; a halophenyl group; an alkoxyphenyl group; a
carboxyalkylphenyl group; a phenylalkynyl group; an alkynyl group;
an alkylglycineethylester group; a styrene group; a thiophene
group; and an alkylaminophospho group; and pharmaceutically
acceptable salts thereof.
41. A tetracycline compound of the formula (VI): 1748wherein:
R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, hydroxyl, halogen, hydrogen, or when taken together the
oxygen of a carbonyl group; R.sup.5 is hydrogen, hydroxyl, or a
prodrug moiety; R.sup.6 is an alkyl or an aryl group, and
pharmaceutically acceptable salts thereof.
42. The tetracycline compound of claim 41, wherein R.sup.4 and
R.sup.4' are each hydrogen.
43. The tetracycline compound of claim 42, wherein R.sup.6 is
alkyl.
44. The tetracycline compound of claim 42, wherein R.sup.6 is
aryl.
45. The tetracycline compound of claims 42, wherein R.sup.6 is an
alkoxyphenyl group, a halophenyl group, a carboxyphenyl group, an
acylphenyl group, a cyanophenyl group, a nitrophenyl group, a
naphthyl group, a dialkylphenyl group, an alkylphenyl group; a
t-butyl group; or an aminoalkanethio group.
46. A tetracycline compound of formula VII: 1749wherein: X is
CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, C.dbd.CR.sup.6'R.sup.6, S,
NR.sup.6, or O; R.sup.2 and R.sup.2' are each independently
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety; R.sup.4 and
R.sup.4' are each independently alkyl, alkenyl, alkynyl, hydroxyl,
halogen, hydrogen, or when taken together the oxygen of a carbonyl
group; R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety; R.sup.5 is hydroxyl, hydrogen,
thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl,
alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
R.sup.6 and R.sup.6' are each independently hydrogen, methylene,
absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; R.sup.7 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, or --(CH.sub.2).sub.0-3NR.sup-
.7cC(.dbd.W')WR.sup.7a; R.sup.9 is hydrogen, nitro, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
arylalkyl, amino, arylalkenyl, arylalkynyl, thionitroso(e.g.,
--N.dbd.S), or --(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a; Z is
CR.sup.9dR.sup.9c, S, NR.sup.9b or O; Z' is O, S, or NR.sup.9f; W
is CR.sup.7dR.sup.7e, S, NR.sup.7b or O; W' is O, NR.sup.7fS;
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.9a,
R.sup.9b, R.sup.9c, R.sup.9d, and R.sup.9e are each independently
hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety; R.sup.8 is
hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and Y' and Y are each independently hydrogen, halogen,
hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts, prodrugs and
esters thereof.
47. The compound of claim 46, wherein R.sup.4 and R.sup.4' are
hydrogen or the oxygen of a carbonyl group, X is CR.sup.6R.sup.6';
R.sup.2, R.sup.2', R.sup.6, R.sup.6', R.sup.10, R.sup.11, and
R.sup.12 are each hydrogen; R.sup.5 is hydroxy or hydrogen; and
R.sup.7 and R.sup.9 are each independently amino, dialkylamino, or
hydrogen.
48. The compound of claim 47, wherein R.sup.4, R.sup.4', and
R.sup.5 are each hydrogen; R.sup.7is hydrogen; and R.sup.9 is
hydrogen or amino.
49. The compound of claim 48, wherein R.sup.8 is halogen, alkyl,
alkenyl, alkynyl, aryl or heteroaryl.
50. A tetracycline compound of the formula (VIII): 1750wherein:
R.sup.5 is hydrogen or hydroxyl; R.sup.6 and R.sup.6' are each
independently hydrogen, methyl, or hydroxyl; R.sup.7 is hydrogen,
R.sup.8 is phenyl, nitrophenyl, halo, or lower alkynyl; and R.sup.9
is hydrogen or amino, and pharmaceutically acceptable salts,
prodrugs and esters thereof.
51. The compound of claim 50, wherein said compound is 8-phenyl
4-dedimethylamino doxycycline, 8-bromo 4-dedimethylamino
doxycycline, 8-(p-nitrophenyl) 4-dedimethylamino doxycycline,
8-ethynyl-9-amino 4-dedimethylamino doxycycline or 8-phenyl-9-amino
4-dedimethylamino doxycycline.
52. A tetracycline compound selected from the group consisting of:
1751175217531754175517561757175817591760176117621763176417651766176717681-
769177017711772177317741775177617771778177917801781178217831784and
pharmaceutically acceptable esters, prodrugs, and salts
thereof.
53. A substituted tetracycline compound selected from the group
listed in Table 2, and pharmaceutically acceptable esters,
prodrugs, and salts thereof.
54. A method for treating a tetracycline responsive state in a
subject, comprising administering to said subject a tetracycline
compound of any one of claims 1, 16, 17, 30, 40, 41, 46, 52, or 53,
such that said subject is treated.
55. The method of claim 54, wherein said tetracycline responsive
state is not a bacterial infection.
56. The method of claim 54, wherein said subject is a human.
57. A pharmaceutical composition comprising a therapeutically
effective amount of a tetracycline compound of any one of claims 1,
16, 17, 30, 40, 41, 46, 52, or 53, and a pharmaceutically
acceptable carrier.
58. The tetracycline compound of any one of claims 1, 16, 17, 30,
40, 41, 46, 52, or 53, wherein said compound is
non-antibacterial.
59. A method for modulating tetracycline efflux, comprising
administering an effective amount of a tetracycline compound, such
that tetracycline efflux is modulated, wherein said tetracycline
compound is of any one of claims 1, 16, 17, 30, 40, 41, 46, 52, or
53.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application Serial No. 60/367,049, entitled "8-Substituted
4-Dedimethylamino Tetracycline Compounds," filed Mar. 21, 2002;
U.S. Provisional Patent Application Serial No. 60/346,930, entitled
"7-Substituted 4-Dedimethylamino Tetracycline Compounds," filed
Jan. 8, 2002; U.S. Provisional Patent Application Serial No.
60/346,929, entitled "7, 9-Substituted 4-Dedimethylamino
Tetracycline Compounds," filed Jan. 8, 2002; U.S. Provisional
Patent Application Serial No. 60/347,065, entitled "9-Substituted
4-Dedimethylamino Minocycline Compounds," filed Jan. 8, 2002; and
U.S. Provisional Patent Application Serial No. 60/346,956, entitled
"13-Substituted 4-Dedimethylamino Methacycline Compounds," filed
Jan. 8, 2002. The entire contents of each of these applications are
hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The development of the tetracycline antibiotics was the
direct result of a systematic screening of soil specimens collected
from many parts of the world for evidence of microorganisms capable
of producing bacteriocidal and/or bacteriostatic compositions. The
first of these novel compounds was introduced in 1948 under the
name chlortetracycline. Two years later, oxytetracycline became
available. The elucidation of the chemical structure of these
compounds confirmed their similarity and furnished the analytical
basis for the production of a third member of this group in 1952,
tetracycline. A new family of tetracycline compounds, without the
ring-attached methyl group present in earlier tetracyclines, was
prepared in 1957 and became publicly available in 1967; and
minocycline was in use by 1972.
[0003] Recently, research efforts have focused on developing new
tetracycline antibiotic compositions effective under varying
therapeutic conditions and routes of administration. New
tetracycline analogues have also been investigated which may prove
to be equal to or more effective than the originally introduced
tetracycline compounds. Examples include U.S. Pat. Nos. 2,980,584;
2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859;
3,957,980; 4,018,889; 4,024,272; and 4,126,680. These patents are
representative of the range of pharmaceutically active tetracycline
and tetracycline analogue compositions.
[0004] Historically, soon after their initial development and
introduction, the tetracyclines were found to be highly effective
pharmacologically against rickettsiae; a number of gram-positive
and gram-negative bacteria; and the agents responsible for
lymphogranuloma venereum, inclusion conjunctivitis, and
psittacosis. Hence, tetracyclines became known as "broad spectrum"
antibiotics. With the subsequent establishment of their in vitro
antimicrobial activity, effectiveness in experimental infections,
and pharmacological properties, the tetracyclines as a class
rapidly became widely used for therapeutic purposes. However, this
widespread use of tetracyclines for both major and minor illnesses
and diseases led directly to the emergence of resistance to these
antibiotics even among highly susceptible bacterial species both
commensal and pathogenic (e.g., pneumococci and Salmonella). The
rise of tetracycline-resistant organisms has resulted in a general
decline in use of tetracyclines and tetracycline analogue
compositions as antibiotics of choice.
SUMMARY OF THE INVENTION
[0005] The invention pertains, at least in part, to 7-substituted
4-dedimethylamino tetracycline compound of Formula I: 1
[0006] wherein:
[0007] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6,
C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
[0008] R.sup.2 and R.sup.2 are each independently hydrogen, alkyl,
alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a
prodrug moiety;
[0009] R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, hydroxyl, halogen, hydrogen, or when taken together the
oxygen of a carbonyl group;
[0010] R.sup.2'R.sup.3, R.sup.10 R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0011] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0012] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0013] R.sup.7 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl,
heterocyclic, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
arylalkyl, amino, amido, arylalkenyl, arylalkynyl, or
--(CH.sub.2).sub.0-3NR.sup.7cC- (.dbd.W')WR.sup.7a;
[0014] R.sup.9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
amido, arylalkenyl, arylalkynyl, thionitroso(e.g., --N.dbd.S), or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a;
[0015] Z is CR.sup.9dR.sup.9e, S, NR or O;
[0016] Z' is O, S, or NR.sup.9f;
[0017] W is CR.sup.7dR.sup.7c, S, NR.sup.7b or O;
[0018] W' is O, NR.sup.7fS;
[0019] R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7d, R.sup.9a,
R.sup.9b , R.sup.9c, R.sup.9d, and R.sup.9e are each independently
hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0020] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0021] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0022] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, amido, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts thereof.
[0023] The invention also pertains to 7-substituted
4-dedimethylamino sancycline compounds of the formula: 2
[0024] wherein:
[0025] R.sup.7 is a fused ring moiety of the formula 3
[0026] where Q is C or a heteroatom; an acylfuranyl group; a tri-,
tetra- or penta- halo substituted phenyl group; an
aminomethylphenyl group; an acylaminomethyl group; an
alkylesterphenyl group; an acylphenyl group; an acylalkynyl group;
an acylalkoxyphenyl group; a methylphenyl group; a dimethylphenyl
group; a carboxyphenyl group; a carboxyalkynyl group; a thiophene
group; a halothiophene group; an alkoxycarbonylphenyl group; an
alkoxyphenyl group; an alkoxyphenylalkynyl group; an alkoxypyridyl
group; an alkylenepyridine group; a cyclopentyl or cyclopentenyl
group; a cyclohexylalkynyl group; a cyclohexenylalkynyl group; a
cyclohexenylhaloalkenyl group; a hydroxycyclohexylalkynyl group; a
phenylalkynyl group; a phenylalkenyl group; an aminoalkynyl group;
a cyclobutylalkenyl group; a pyridylalkynyl group; a pyridylalkenyl
group; a nitrophenylalkynyl group; a nitrophenylalkenyl group; a
cyanoalkynyl group; an alkynyl group; a cyanoalkenyl group; a
cyanophenyl group; a dialkylamidoalkenyl group; a
dialkylamidophenyl group; an aminophenylethyl group; an
aminophenylethynyl group; a haloethenyl group; a halophenylalkynyl
group; or an alkylester-substituted pentenyl group; and
pharmaceutically acceptable salts thereof.
[0027] In an embodiment, the invention pertains to 7, 9-substituted
4-dedimethylamino tetracycline compounds of Formula III: 4
[0028] wherein:
[0029] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or
O;
[0030] R.sup.2 and R.sup.2' are each independently hydrogen, alkyl,
alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a
prodrug moiety;
[0031] R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, hydroxyl, halogen, hydrogen, or when taken together the
oxygen of a carbonyl group;
[0032] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0033] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0034] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0035] R.sup.7 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, or
--(CH.sub.2).sub.0-3NR.sup.7cC(.dbd.W))WR.sup.7a;
[0036] R.sup.9 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a;
[0037] Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O;
[0038] Z' is O, S, or NR.sup.9f,
[0039] W is CR.sup.7dR.sup.7e, S, NR or O;
[0040] W' is O, NR.sup.7fS;
[0041] R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.9a,
R.sup.9b, R.sup.9c, R.sup.9d, and R.sup.9e are each independently
hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0042] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0043] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0044] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts thereof.
[0045] The invention pertains, at least in part, to
4-dedimethylamino tetracycline compounds of formula IV: 5
[0046] wherein:
[0047] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or
O;
[0048] R.sup.2, R.sup.7' and R.sup.7" are each hydrogen, alkyl,
alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a
prodrug moiety;
[0049] R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, aryl, hydroxyl, alkoxy halogen, hydrogen, or taken
together to form the oxygen of a carbonyl;
[0050] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0051] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0052] R.sup.6 and R.sup.6' are independently hydrogen, methylene,
absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0053] R.sup.7is NR.sup.7'R.sup.7", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0054] R.sup.9 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a;
[0055] Z is CR.sup.9dR.sup.9e, S, NR or O;
[0056] Z' is NR.sup.9f, O or S;
[0057] R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e and
R.sup.9f are each independently hydrogen, acyl, alkyl, alkenyl,
alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a
prodrug moiety;
[0058] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0059] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0060] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts, esters and
prodrugs thereof.
[0061] The invention also pertains, at least in part, to
9-substituted 4-dedimethylamino tetracycline compounds of the
formula (V): 6
[0062] wherein:
[0063] R.sup.7' and R.sup.7" are each alkyl; and
[0064] R.sup.9 is a pyridylethynyl group; an alkenylcarbamate
group; a halo group; an alkylacrylate group; a naphthyl group; a
haloacetyl group; an alkyl carbamate group; a cyclopentyl or
cyclopentenyl group; a benzofuranyl group; a phenylpropiononeamino
group; a tosylamino group; a methoxypyridyl group; an alkeneamino
group; an N-t-butyl group; a t-butylamide group; a
hydroxybutylamino group; a hydroxypropylamino group; a phenyl
group; a nitrophenyl group; a nitrophenyl alkynyl group; an
aminophenyl group; an alkoxyphenyl group; a halophenyl urea group;
a cyanophenyl group; a carboxyphenyl group; an acylphenyl group; an
alkylphenyl group; a halophenyl group; an alkoxyphenyl group; a
carboxyalkylphenyl group; a phenylalkynyl group; an alkynyl group;
an alkylglycineethylester group; a styrene group; a thiophene
group; and an alkylaminophospho group; and pharmaceutically
acceptable salts, esters and prodrugs thereof.
[0065] In another embodiment, the invention pertains to
13-substituted tetracycline compounds of the formula (VI): 7
[0066] wherein:
[0067] R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, hydroxyl, halogen, hydrogen, or when taken together the
oxygen of a carbonyl group;
[0068] R.sup.5 is hydrogen, hydroxyl, or a prodrug moiety;
[0069] R.sup.6 is an alkyl or an aryl group, and pharmaceutically
acceptable salts, esters, and prodrugs thereof.
[0070] In a further embodiment, R.sup.6 is a phenyl group, i.e., an
alkoxyphenyl group, a halophenyl group, a carboxyphenyl group, an
acylphenyl group, a cyanophenyl group, a nitrophenyl group, a
naphthyl group, a dialkylphenyl group, or an alkylphenyl group; a
t-butyl group; or an aminoalkanethio group.
[0071] In another embodiment, the invention pertains, at least in
part, to 8-substituted 4-dedimethylamino tetracycline compound of
Formula VII: 8
[0072] wherein:
[0073] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6,
C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
[0074] R.sup.2 and R.sup.2' are each independently hydrogen, alkyl,
alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a
prodrug moiety;
[0075] R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, hydroxyl, halogen, hydrogen, or when taken together the
oxygen of a carbonyl group;
[0076] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0077] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0078] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0079] R.sup.7 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, or
--(CH.sub.2).sub.0-3NR.sup.7cC(.dbd.W')WR.sup.7a;
[0080] R.sup.9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, thionitroso(e.g., --N.dbd.S), or
--(CH.sub.2).sub.0-3NR.sup.- 9cC(=Z')ZR.sup.9a;
[0081] Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O;
[0082] Z' is O, S, or NR.sup.9f;
[0083] W is CR.sup.7dR.sup.7e, S, NR.sup.7b or O;
[0084] W' is O, NR.sup.7fS;
[0085] R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.9a,
R.sup.9b, R.sup.9c, R.sup.9d, and R.sup.9e, are each independently
hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0086] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0087] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0088] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts, prodrugs and
esters thereof.
[0089] In another embodiment, the invention pertains, at least in
part, to 8-substituted 4-dedimethylamino tetracycline compounds of
the formula: 9
[0090] wherein:
[0091] R.sup.5 is hydrogen or hydroxyl;
[0092] R.sup.6 and R.sup.6' are each independently hydrogen,
methyl, or hydroxyl;
[0093] R.sup.7 is hydrogen,
[0094] R.sup.8 is phenyl, nitrophenyl, halo, or lower alkynyl;
and
[0095] R.sup.9 is hydrogen or amino, and pharmaceutically
acceptable salts, prodrugs and esters thereof.
[0096] The invention also pertains to a method for treating a
tetracycline responsive state in a subject, by administering to the
subject a 4-dedimethylamino tetracycline compound of the invention
(e.g., of Formula I, II, III, IV, V, VI, VII, VIII or Table 2),
such that the tetracycline responsive state is treated. In an
embodiment, the tetracycline responsive state is not a bacterial
infection.
[0097] The invention also includes pharmaceutical compositions
comprising an effective amount of a 4-dedimethylamino tetracycline
compound of the invention (e.g., of Formula I, II, III, IV, V, VI,
VII, VIII or Table 2), and, optionally, a pharmaceutically
acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
[0098] The present invention pertains, at least in part, to novel
4-dedimethylamino tetracycline compounds. These tetracycline
compounds can be used to treat numerous tetracycline
compound-responsive states, such as, but not limited to, bacterial
infections and neoplasms, as well as other known applications for
minocycline and tetracycline compounds in general, such as blocking
tetracycline efflux and modulation of gene expression.
[0099] The term "tetracycline compound" includes many compounds
with a similar ring structure to tetracycline. Examples of
tetracycline compounds include: tetracycline, chlortetracycline,
oxytetracycline, demeclocycline, methacycine, sancycline,
doxycycline, and minocycline. Other derivatives and analogues
comprising a similar four ring structure are also included. The
term also includes 4-dedimethylamino tetracycline compounds. Table
1 depicts tetracycline and several known tetracycline
derivatives.
1TABLE I 10 11 12 13
I. 7-Substituted 4-Dedimethylamino Tetracycline Compounds
[0100] The term "7-substituted 4-dedimethylamino tetracycline
compounds" includes tetracycline compounds with substitution at the
7 position. In one embodiment, the substitution at the 7- position
enhances the ability of the tetracycline compound to perform its
intended function, e.g., treat tetracycline responsive states. In
an embodiment, the 7-substituted tetracycline compound is
7-substituted 4-dedimethylamino tetracycline (e.g., wherein R.sup.4
and R.sup.4' are hydrogen, R.sup.5is hydrogen and X is
CR.sup.6R.sup.6', wherein R.sup.6 is methyl and R.sup.6' is
hydroxy); 7-substituted 4-dedimethylamino doxycycline (e.g.,
wherein R.sup.4 and R.sup.4' are hydrogen, R.sup.5 is hydroxyl and
X is CR.sup.6R.sup.6', wherein R.sup.6 is methyl and R.sup.6' is
hydrogen); 7-substituted dedimethylamino tetracycline compounds,
wherein X is CR.sup.6R.sup.6', R.sup.4, R.sup.4', R.sup.5,
R.sup.6', and R.sup.6 are hydrogen; or 7- substituted
4-dedimethylamino sancycline (wherein R.sup.4 and R.sup.4' are
hydrogen; R.sup.5 is hydrogen and X is CR.sup.6R.sup.6' wherein
R.sup.6 and R.sup.6' are hydrogen atoms.
[0101] The invention pertains, at least in part, to 7-substituted
4-dedimethylamino tetracycline compound of Formula I: 14
[0102] wherein:
[0103] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6,
C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
[0104] R.sup.2 and R.sup.2' are each independently hydrogen, alkyl,
alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a
prodrug moiety;
[0105] R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, hydroxyl, halogen, hydrogen, or when taken together the
oxygen of a carbonyl group;
[0106] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0107] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0108] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0109] R.sup.7 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl,
heterocyclic, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
arylalkyl, amino, amido, arylalkenyl, arylalkynyl, or
--CH.sub.2).sub.0-3NR.sup.7cC(- .dbd.W')WR.sup.7a;
[0110] R.sup.9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
amido, arylalkenyl, arylalkynyl, thionitroso(e.g., --N.dbd.S), or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a;
[0111] Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O;
[0112] Z' is O, S, or NR.sup.9f;
[0113] W is CR.sup.7dR.sup.7e, S, NR.sup.7b or O;
[0114] W' is O, NR.sup.7fS;
[0115] R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.9a,
R.sup.9b, R.sup.9c, R.sup.9d, and R.sup.9e are each independently
hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0116] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0117] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0118] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, amido, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts- thereof.
[0119] In certain embodiment, R.sup.7 is not nitro or amino.
[0120] In an embodiment, X is CR.sup.6R.sup.6'; R.sup.2, R.sup.2',
R.sup.6, R.sup.6', R.sup.8, R.sup.9, R.sup.10, R.sup.11, and
R.sup.12 are each hydrogen; R.sup.4 and R.sup.4' are hydrogen,
halogen (e.g., chlorine, fluorine, bromine, iodine, etc.), hydroxy,
or when taken together the oxygen of a carbonyl group; and R.sup.5
is hydroxy or hydrogen.
[0121] In an embodiment, R.sup.7 is aryl. Examples of aryl R.sup.7
groups include substituted or unsubstituted phenyl. The phenyl
R.sup.7 group can be substituted with any substituent which allow
the tetracycline compound to perform its intended function.
Examples of substituents include, but are not limited to, alkyl,
alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,
alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl.
[0122] In a further embodiment, the phenyl R.sup.7 group is
substituted with substituted or unsubstituted alkyl. Examples of
substituents of the alkyl include heterocycles such as, morpholine,
piperdine, and pyrrolidine. In another further embodiment, the
phenyl R.sup.7 group is substituted with an amino group. The amino
group also may be further substituted e.g., with an alkyl, alkenyl,
alkynyl, carbonyl, alkoxy or aryl (e.g., substituted or
unsubstituted, heteroaryl, phenyl, etc.) group. The phenyl amino
substituent may be substituted with any substituent or combination
of substituents which allow it to perform its intended function.
Examples of such substituents include halogens (e.g., fluorine,
chlorine, bromine, iodine, etc.), amino (e.g., which can in turn be
substituted with an alkyl, carbonyl, alkenyl, alkynyl, or aryl
moiety), and arylamino (e.g., phenylamino).
[0123] The R.sup.7 phenyl group may also be substituted with alkoxy
groups. Examples of alkoxy groups include, but are not limited to,
methoxy, ethoxy, propoxy, butoxy, perfluoromethoxy,
perchloromethoxy, methylenedioxy, etc. The phenyl group may also be
substituted with an amide group such as a carbamate moiety (e.g.,
an alkoxycarbonylamino group).
[0124] The aryl group R.sup.7 group also may be substituted or
unsubstituted biaryl, e.g., naphthyl, fluorenyl, etc. The biaryl
R.sup.7 group can be substituted with any substituent which allow
it to perform its intended function. Examples of substituents
include but are not limited to, alkyl, alkenyl, halogen, hydroxyl,
alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy,
arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl.
[0125] In an embodiment, the substituent is amino or formyl.
[0126] The aryl R.sup.7 group also may be heteroaryl. Examples of
heteroaryl R.sup.7 moieties include, but are not limited to,
furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl,
isoquinolinyl, pyridinyl, pyrazolyl, benzodioxazolyl, benzoxazolyl,
benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl,
thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl,
isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, and
deazapurinyl. In certain embodiments, the heteroaryl R.sup.7 group
is thiazolyl, thiophenyl, or furanyl.
[0127] R.sup.7 also may be substituted or unsubstituted alkyl. The
alkyl group can be a straight or branched chain, e.g., methyl,
ethyl, i-propyl, n-propyl, n-butyl, i-butyl, t-butyl, pentyl,
hexyl. etc. The alkyl group may also comprise a ring, e.g., a
cycloalkyl (e.g., cyclopentyl, cyclohexyl, cyclopropyl, or
cyclobutyl). The alkyl R.sup.7 group may be substituted with any
substituent or combination of substituents which allows the
compound to perform its intended function. Examples of substituents
include, but are not limited to, alkenyl, halogen, hydroxyl,
alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy,
arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl.
[0128] In certain embodiments, the alkyl group is substituted with
an amino, hydroxy, carboxy, carbonyl (e.g., substituted carbonyl,
e.g., morpholinyl carbonyl), heterocyclic or aryl groups. Examples
heterocyclic groups include, for example, furanyl, imidazolyl,
benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl,
benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl,
methylenedioxyphenyl, indolyl, thienyl, pyridinyl, pyrazolyl,
pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl,
naphthridinyl, thiazolyl, isothiazolyl, and deazapurinyl. In a
further embodiment, the aryl group is pyridinyl.
[0129] In a further embodiment, the aralkyl R.sup.7 group comprises
substituted or unsubstituted phenyl. This phenyl group also may be
substituted with any substituent which allows it to perform its
intended function. Examples of substituents include, but are not
limited to, sulfonamido, alkyl, and the other substituents listed
supra for alkyl R.sup.7 groups.
[0130] R.sup.7 also may be substituted or unsubstituted alkenyl.
Examples of substituents include those which allow the compound to
perform its intended function. Examples of substituents include but
are not limited to alkyl, halogen, hydroxyl, alkoxy,
alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy,
alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl
aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,
aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl,
silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl,
phosphonato, phosphinato, cyano, amino, acylamino, amido, imino,
sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano,
azido, heterocyclyl, alkylaryl, aryl and heteroaryl moieties.
[0131] In a further embodiment, the alkenyl R.sup.7 group is
substituted with an aminocarbonyl (e.g., alkylaminocarbonyl,
dialkylaminocarbonyl, dimethylaminocarbonyl) or alkoxycarbonyl. The
alkenyl R.sup.7 group also may be substituted with one or more
halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxy
groups, heteroaryl groups (e.g., furanyl, imidazolyl,
benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl,
benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl,
methylenedioxyphenyl, indolyl, thienyl, pyridinyl, pyrazolyl,
pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl,
naphthridinyl, thiazolyl, isothiazolyl, deazapurinyl, etc.). In an
embodiment, the heteroaryl substituent s thiazolyl.
[0132] In a further embodiment, the alkenyl R.sup.7 group is
substituted with a substituted or unsubstituted phenyl. The phenyl
can be substituted with any substituent which allows it to perform
its intended function. Examples of substituents include those
listed supra for other phenyl moieties. Other examples of
substituents include, but are not limited to, halogens (e.g.,
fluorine, chlorine, bromine, iodine, etc.), alkoxy (e.g., methoxy,
ethoxy, propoxy, perfluoromethyl, perchloromethyl, etc.), hydroxy,
or alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.)
groups.
[0133] Another example of R.sup.7 include substituted and
unsubstituted alkynyls. The alkynyl moieties can be substituted
with any substituted or combination of substituents which allow the
tetracycline compound of the invention to perform its intended
function. Examples of the substituents include, but are not limited
to alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,
alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulthydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl moieties.
[0134] In an embodiment, the alkynyl R.sup.7 moiety is substituted
with an aryl, e.g., substituted or unsubstituted heteroaryl,
phenyl, etc. This aryl moiety may be substituted with any
substituent or combinations of substituents listed supra for the
alkynyl R.sup.7 moiety. Examples of advantageous substituents
include, but are not limited to, carbonylamino (e.g.,
alkylcarbonylamino, dialkylcarbonylamino, arylcarbonylamino, etc.)
and sulphonamido groups.
[0135] In another embodiment, the alkynyl R.sup.7 group is
substituted with a tetracycline moiety. The term "tetracycline
moiety" includes a four ring tetracycline ring system as described
above. This may be connected to the alkynyl R.sup.7 group through a
linker of 1-20 atoms. The linker may be attached to the
tetracycline moiety at any position on that ring system which is
convenient or allows the compound to perform its intended function.
In a certain embodiment, the tetracycline moiety is attached to the
linker at its 7 position.
[0136] Other examples of R.sup.7 moieties include substituted and
unsubstituted alkylcarbonyl amino, sulfonamido, imino and carbonyl
moieties. The carbonyl moieties may be substituted with a
substituted or unsubstituted alkyl group. Examples of possible
substituents of the alkyl group include, but are not limited to,
aryl moieties such as phenyl and heteroaryls (e.g., pyridinyl,
etc.). Examples of substituents of the imino group include, but are
not limited to, hydroxy and alkoxy groups.
[0137] In another embodiment, R.sup.7 is
NR.sup.7c(C.dbd.W')WR.sup.7a. Examples of tetracycline compounds of
the invention include compounds wherein R.sup.7c is hydrogen, W' is
oxygen and W is oxygen. In certain embodiments, R.sup.7a is
substituted or unsubstituted phenyl. Examples of substituents
include, but are not limited to, alkyl, halogen, hydroxyl, alkoxy,
alkylcarbonyloxy, alkyloxycarbonyl, carboxy, alkylcarbonylamino,
arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, crylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl.
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl. In a further embodiment, R.sup.7a
is substituted or unsubstituted alkyl.
[0138] The invention also pertains to 7-substituted
4-dedimethylamino sancycline compounds of the formula: 15
[0139] wherein:
[0140] R.sup.7 is a fused ring moiety of the formula 16
[0141] where Q is C or a heteroatom; an acylfuranyl group; a tri-,
tetra- or penta- halo substituted phenyl group; an
aminomethylphenyl group; an acylaminomethyl group; an
alkylesterphenyl group; an acylphenyl group; an acylalkynyl group;
an acylalkoxyphenyl group; a methylphenyl group; a dimethylphenyl
group; a carboxyphenyl group; a carboxyalkynyl group; a thiophene
group; a halothiophene group; an alkoxycarbonylphenyl group; an
alkoxyphenyl group; an alkoxyphenylalkynyl group; an alkoxypyridyl
group; an alkylenepyridine group; a cyclopentyl or cyclopentenyl
group; a cyclohexylalkynyl group; a cyclohexenylalkynyl group; a
cyclohexenylhaloalkenyl group; a hydroxycyclohexylalkynyl group; a
phenylalkynyl group; a phenylalkenyl group; an aminoalkynyl group;
a cyclobutylalkenyl group; a pyridylalkynyl group; a pyridylalkenyl
group; a nitrophenylalkynyl group; a nitrophenylalkenyl group; a
cyanoalkynyl group; an alkynyl group; a cyanoalkenyl group; a
cyanophenyl group; a dialkylamidoalkenyl group; a
dialkylamidophenyl group; an aminophenylethyl group; an
aminophenylethynyl group; a haloethenyl group; a halophenylalkynyl
group; or an alkylester-substituted pentenyl group; and
pharmaceutically acceptable salts thereof.
[0142] The term "7-substituted 4-dedimethylamino sancycline
compounds" includes sancycline compounds with a substituent at the
7 position, as described in formula I and a substituent other than
dimethylamino at the 4 position.
[0143] In a further embodiment, R.sup.7 is a fused ring moiety of
the formula 17
[0144] where Q is C or a heteroatom. Examples of 4-dedimethylamino
sancycline compounds with this R.sup.7 substituent include
7-(2'-benzofuran) 4-dedimethylamino sancycline.
[0145] In yet another embodiment, R.sup.7 is an acylfuranyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(3'-formylfuranyl) 4-dedimethylamino
sancycline.
[0146] In yet another embodiment, R.sup.7 is a tri-, tetra- or
penta- halo substituted phenyl group. Examples of 4-dedimethylamino
sancycline compounds with this R.sup.7 substituent include
7-(2',3',4',5',6'-pentafl- uorophenyl) 4-dedimethylamino
sancycline.
[0147] In yet another embodiment, R.sup.7 is an aminomethylphenyl
4-dedimethylamino group. Examples of sancycline compounds with this
R.sup.7 substituent include 7-(4'-aminomethylphenyl)
4-dedimethylamino sancycline.
[0148] In yet another embodiment, R.sup.7 is an acylaminomethyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(4'-formylaminomethylphenyl) 4
-dedimethylamino sancycline.
[0149] In yet another embodiment, R.sup.7 is an alkylesterphenyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(4'-carboxyphenyl methylester)
4-dedimethylamino sancycline and 7-(2'-carboxyphenylethylester)
4-dedimethylamino sancycline.
[0150] In yet another embodiment, R.sup.7 is an alkylphenyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(4'-tolyl) 4-dedimethylamino
sancycline.
[0151] In yet another embodiment, R.sup.7 is an acylphenyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(3'-formylphenyl) 4-dedimethylamino
sancycline, 7-(4'-formylphenyl) 4-dedimethylamino sancycline,
7-(3'-acetylphenyl) 4-dedimethylamino sancycline,
7-(2'-acetylphenyl) 4-dedimethylamino sancycline,
7-(3'-acetylphenyl) 4-dedimethylamino sancycline, and
7-(4'-acetylphenyl) 4-dedimethylamino sancycline.
[0152] In yet another embodiment, R.sup.7 is an acylalkoxyphenyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(3'-formyl-6'-methoxyphenyl)
4-dedimethylamino sancycline.
[0153] In yet another embodiment, R.sup.7 is a methylphenyl group.
Examples of sancycline compounds with this R.sup.7 substituent
include 7-(4'-methylphenyl) 4-dedimethylamino sancycline.
[0154] In yet another embodiment, R.sup.7 is a dimethylphenyl
group. Examples of sancycline compounds with this R.sup.7
substituent include 7-(3',5'-dimethylphenyl) 4-dedimethylamino
sancycline.
[0155] In yet another embodiment, R.sup.7 is a carboxyphenyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(3-carboxyphenyl) 4-dedimethylamino
sancycline.
[0156] In yet another embodiment, R.sup.7 is a carboxyalkynyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(carboxyethynyl) 4-dedimethylamino
sancycline.
[0157] In yet another embodiment, R.sup.7 is a thiophene group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(3-thiophene) 4-dedimethylamino
sancycline, 7-(3'-methyl-2'-thiophene) 4-dedimethylamino
sancycline, and 7-(3-methyl-5-thiophene) 4-dedimethylamino
sancycline.
[0158] In yet another embodiment, R.sup.7 is a halothiophene group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(3'-chloro-2'-thiophene)
4-dedimethylamino sancycline and 7-(4'-chloro-2'-thiophene)
4-dedimethylamino sancycline.
[0159] In yet another embodiment, R.sup.7 is an
alkoxycarbonylphenyl group. Examples of 4-dedimethylamino
sancycline compounds with this R.sup.7 substituent include
7-(2'-ethoxycarbonylphenyl) 4-dedimethylamino sancycline.
[0160] In yet another embodiment, R.sup.7 is an alkoxyphenyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(2'-ethoxyphenyl) 4-dedimethylamino
sancycline, 7-(3'-ethoxyphenyl) 4-dedimethylamino sancycline,
7-(4'-methoxyphenyl) 4-dedimethylamino sancycline, and
7-(2',5'-dimethoxyphenyl) 4-dedimethylamino sancycline.
[0161] In yet another embodiment, R.sup.7 is an alkoxyphenylalkynyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(4'-methoxyphenylethynyl)
4-dedimethylamino sancycline.
[0162] In yet another embodiment, R.sup.7 is an alkoxypyridyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(4'-methoxy-5'-pyridyl)
4-dedimethylamino sancycline.
[0163] In yet another embodiment, R.sup.7 is a cyclopentyl or
cyclopentenyl group. Examples of 4-dedimethylamino sancycline
compounds with this R.sup.7 substituent include 7-(cyclopentenyl)
4-dedimethylamino sancycline.
[0164] In yet another embodiment, R.sup.7 is a cyclohexylalkynyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(cyclohexylethynyl) 4-dedimethylamino
sancycline.
[0165] In yet another embodiment, R.sup.7 is a cyclohexenylalkynyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(1-ethynyl-1-cyclohexyl)
4-dedimethylamino sancycline.
[0166] In yet another embodiment, R.sup.7 is a
cyclohexenylhaloalkenyl group. Examples of 4-dedimethylamino
sancycline compounds with this R.sup.7 substituent include
7-(1-chlorovinyl-1-cyclohexyl) 4-dedimethylamino sancycline.
[0167] In yet another embodiment, R.sup.7 is a
hydroxycyclohexylalkynyl group. Examples of 4-dedimethylamino
sancycline compounds with this R.sup.7 substituent include
7-(1-ethynyl-1-hydroxycyclohexyl) 4-dedimethylamino sancycline.
[0168] In yet another embodiment, R.sup.7 is a phenylalkynyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(phenylethynyl) 4-dedimethylamino
sancycline, 7-(tolylethynyl) 4-dedimethylamino sancycline, and
7-(4-methoxyphenylethynyl) 4-dedimethylamino sancycline.
[0169] In yet another embodiment, R.sup.7 is a phenylalkenyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(2-vinylpyridyl) 4-dedimethylamino
sancycline and 7-(vinylphenyl) 4-dedimethylamino sancycline.
[0170] In yet another embodiment, R.sup.7 is an aminoalkynyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(dimethylaminoethynyl)
4-dedimethylamino sancycline.
[0171] In yet another embodiment, R.sup.7is a cyclobutylalkenyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(cyclobutylmethenyl)
4-dedimethylamino sancycline.
[0172] In yet another embodiment, R.sup.7 is a pyridylalkynyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(2-pyridylethynyl) 4-dedimethylamino
sancycline and 7-(3-pyridylethynyl) 4-dedimethylamino
sancycline.
[0173] In yet another embodiment, R.sup.7 is a pyridylalkenyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(4-pyridylethenyl) 4-dedimethylamino
sancycline.
[0174] In yet another embodiment, R.sup.7 is a nitrophenylalkynyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(4-nitrophenylethynyl)
4-dedimethylamino sancycline.
[0175] In yet another embodiment, R.sup.7 is a nitrophenylalkenyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(4-nitrostyryl) 4-dedimethylamino
sancycline.
[0176] In yet another embodiment, R.sup.7 is an alkynyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(ethynyl) 4-dedimethylamino
sancycline.
[0177] In yet another embodiment, R.sup.7 is a cyanoalkynyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(cyano-1-pentynyl) 4-dedimethylamino
sancycline.
[0178] In yet another embodiment, R.sup.7 is a cyanoalkenyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include and 7-(cyanohexenyl) 4-dedimethylamino
sancycline.
[0179] In yet another embodiment, R.sup.7 is a cyanophenyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(3-cyanophenyl) 4-dedimethylamino
sancycline and 7-(4-cyanophenyl) 4-dedimethylamino sancycline.
[0180] In yet another embodiment, R.sup.7 is a
hydroxylphenylethynyl group. Examples of 4-dedimethylamino
sancycline compounds with this R.sup.7 substituent include
7-(3-hydroxylphenylethynyl) 4-dedimethylamino sancycline.
[0181] In yet another embodiment, R.sup.7 is a dialkylamidoalkenyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(N,N-dimethylacrylamide)
4-dedimethylamino sancycline and 7-(dimethylaminophenyl)
4-dedimethylamino sancycline.
[0182] In yet another embodiment, R.sup.7 is a dialkylamidophenyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(3-dimethylamidophenyl)
4-dedimethylamino sancycline.
[0183] In yet another embodiment, R.sup.7 is an aminophenylethyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(4-aminophenylethyl)
4-dedimethylamino sancycline.
[0184] In yet another embodiment, R.sup.7 is an aminophenylethynyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(4-aminophenylethynyl)
4-dedimethylamino sancycline.
[0185] In yet another embodiment, R.sup.7 is a haloethenyl group.
Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(2-chloroethenyl) 4-dedimethylamino
sancycline.
[0186] In yet another embodiment, R.sup.7 is a halophenylalkynyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(2-fluorophenylethenyl)
4-dedimethylamino sancycline.
[0187] In yet another embodiment, R.sup.7 is an
alkylester-substituted pentenyl group. Examples of
4-dedimethylamino sancycline compounds with this R.sup.7
substituent include 7-(1-iodo-1,3-dicarboethoxy-1,3-butadien- e)
4-dedimethylamino sancycline.
[0188] In yet another embodiment, R.sup.7 is an aminophenylalkynyl
group. Examples of 4-dedimethylamino sancycline compounds with this
R.sup.7 substituent include 7-(4-aminophenylvinyl)
4-dedimethylamino sancycline.
[0189] The invention also pertains to the tetracycline compounds
shown below: 1819202122232425262728293031323334
[0190] Also included are salts, esters and prodrugs of the
compounds shown above and in Table 2.
II. 7,9-Substituted 4-Dedimethylamino Tetracycline Compounds
[0191] The present invention pertains, at least in part, to novel
7,9-substituted 4-dedimethylamino tetracycline compounds. These
tetracycline compounds can be used to treat numerous tetracycline
compound-responsive states, such as bacterial infections and
neoplasms, as well as other known applications for minocycline and
tetracycline compounds in general, such as blocking tetracycline
efflux and modulation of gene expression.
[0192] The term "7,9-substituted 4-dedimethylamino tetracycline
compounds" includes tetracycline compounds with substitution at the
7 and 9-positions and a substituent other than dimethylamino at the
4 position. In one embodiment, the substitution at the 7- and
9-positions enhances the ability of the tetracycline compound to
perform its intended function, e.g., treat tetracycline responsive
states. In an embodiment, the 7,9-substituted tetracycline compound
is 7,9-substituted tetracycline (e.g., wherein R.sup.4 is
NR.sup.4'R.sup.4"; R.sup.4' and R.sup.4" are methyl, R.sup.5 is
hydrogen and X is CR.sup.6R.sup.6', wherein R.sup.6 is methyl and
R.sup.6' is hydroxy); 7,9-substituted doxycycline (e.g., wherein
R.sup.4 is NR.sup.4'R.sup.4"; R.sup.4' and R.sup.4" are methyl,
R.sup.5 is hydroxyl and X is CR.sup.6R.sup.6', wherein R.sup.6 is
methyl and R.sup.6' is hydrogen); or 7,9-substituted sancycline
(wherein R.sup.4 is NR.sup.4'R.sup.4"; R.sup.4' and R.sup.4" and
R.sup.4" are methyl; R.sup.5 is hydrogen and X is CR.sup.6R.sup.6'
wherein R.sup.6 and R.sup.6' are hydrogen atoms. In an embodiment,
the substitution at the 7 position of the 7,9-substituted
tetracycline compound is not chlorine or trimethylamino. In one
embodiment, R.sup.4 and R.sup.4' are each hydrogen or the oxygen of
a carbonyl group.
[0193] The 7,9-substituted 4-dedimethylamino tetracycline compounds
of the invention include compounds of Formula I: 35
[0194] wherein:
[0195] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or
O;
[0196] R.sup.2 and R.sup.2' are each independently hydrogen, alkyl,
alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a
prodrug moiety;
[0197] R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, hydroxyl, halogen, hydrogen, or when taken together the
oxygen of a carbonyl group;
[0198] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0199] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0200] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0201] R.sup.7 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, or
--(CH.sub.2).sub.0-3NR.sup.7cC(.dbd.W')WR.sup.7a;
[0202] R.sup.9 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a;
[0203] Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O;
[0204] Z' is O, S, or NR.sup.9f;
[0205] W is CR.sup.7dR.sup.7e, S, NR.sup.7b or O;
[0206] W' is O, NR.sup.7fS;
[0207] R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.9a,
R.sup.9b, R.sup.9c, R.sup.9d, and R.sup.9e are each independently
hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0208] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0209] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0210] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts thereof.
[0211] The tetracycline compounds of the invention include, for
example, compounds wherein X is CR.sup.6R.sup.6'; R.sup.4 and
R.sup.4' are hydrogen or the oxygen of a carbonyl group; R.sup.2,
R.sup.2', R.sup.6, R.sup.6', R.sup.8, R.sup.10, R.sup.11, and
R.sup.12 are each hydrogen; R.sup.4' and R.sup.4" are lower alkyl;
and R.sup.5 is hydroxy or hydrogen. In an embodiment, R.sup.4 and
R.sup.4' are each hydrogen and R.sup.5 is hydrogen. The
tetracycline compounds of the invention include each possible
combination of R.sup.7 and R.sup.9 substituents discussed
below.
[0212] In an embodiment, R.sup.7 is aryl (e.g., heteroaryl or
substituted or unsubstituted phenyl). The phenyl R.sup.7 group may
be substituted with one or more substituents. Examples of
substituents of phenyl R.sup.7 groups include alkyl, alkenyl,
halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl,
arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl. In certain embodiments, the
substituent is substituted or unsubstituted alkyl (e.g., methyl,
ethyl, propyl, butyl, etc.), nitro, halogen (e.g., fluorine,
bromine, chlorine, iodine, etc.), amino (e.g., unsubstituted amino,
alkyl amino, dialkylamino (e.g., dimethylamino), or alkoxy
(methylenedioxy or methoxy).
[0213] R.sup.7 also may be substituted or unsubstituted alkyl(e.g.,
methyl, ethyl, i-propyl, n-propyl, t-butyl, i-butyl, n-butyl,
pentyl, n-pentyl, n-hexyl, or hexyl). The alkyl may be branched or
straight chain and may comprise a ring, e.g., a cycloalkyl ring,
e.g., cyclohexyl ring.
[0214] The alkyl R.sup.7 group may be substituted with any
substituent which allows the tetracycline compound to perform its
intended function. Examples of substituents include, but are not
limited to, alkenyl, halogen (e.g., fluorine, chlorine, bromine,
iodine, etc.), hydroxyl, alkoxy (e.g., methoxy, ethoxy,
perchloromethoxy, perfluoromethoxy, etc.), alkylcarbonyloxy,
alkyloxycarbonyl, arylcarbonyloxy, arylcarbonylamino,
alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl
aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,
aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl,
silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl,
phosphonato, phosphinato, cyano, amino, acylamino, amido, imino,
sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano,
azido, heterocyclyl, alkylaryl, aryl and heteroaryl.
[0215] Examples of heterocyclic substituents include
N-isoindole-[1,3]-dione (e.g., phthalimide). In an embodiment, the
substituent is arylcarbonylamino, e.g., heteroaryl carbonyl amino.
The heteroaryl group may be, for example, pyridinyl. Other examples
of substituents include amino or carboxylate.
[0216] In another embodiment, R.sup.7 is acyl, e.g., acetyl.
[0217] In yet another embodiment, R.sup.7 is substituted or
unsubstituted alkynyl. Examples of substituents include those which
allow the tetracycline compound to perform its intended function.
Examples of substituents include, but are not limited to, alkyl
(e.g., methyl, ethyl, propyl, butyl, etc.), alkenyl, halogen,
hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl,
arylcarbonyloxy, arylcarbonylamino, alkoxycarbonylamino,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl.
[0218] In a further embodiment, the aryl substituent is substituted
or unsubstituted phenyl. The phenyl also may be further substituted
with one or more substituents which allow the compound to perform
its intended function. Examples of phenyl substituents include, but
are not limited to, alkoxy (e.g., methoxy).
[0219] The tetracycline compounds of the invention include
compounds wherein R.sup.9 is substituted or unsubstituted aryl
(e.g., carbocyclic or heteroaryl). In an embodiment, R.sup.9 is
substituted or unsubstituted phenyl. The substituted phenyl group
can be substituted with any substituent or combination of
substituents which allows the compound to perform its intended
function. Examples of substituents include, but are not limited to,
alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,
alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl.
[0220] In a further embodiment, the phenyl R.sup.9 substituent is
substituted or unsubstituted alkyl, nitro, halogen, amino, or
alkoxy (e.g., methylenedioxy).
[0221] The invention also includes compounds wherein R.sup.9 is
substituted or unsubstituted alkyl (e.g., methyl, ethyl, i-propyl,
n-propyl, i-butyl, t-butyl, n-butyl, pentyl, hexyl, etc.). The
alkyl group may be substituted with any substituent that allows the
compound to perform its intended function. Examples of the
substituents include, but are not limited to, alkenyl, halogen,
hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl,
arylcarbonyloxy, arylcarbonylamino, alkoxycarbonylamino,
alkoxycarbonyloxy, aryloxycarbonyloxy, alkylcarbonylamino,
carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl
aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,
aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl,
silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl,
phosphonato, phosphinato, cyano, amino, acylamino, amido, imino,
sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano,
azido, heterocyclyl, alkylaryl, aryl and heteroaryl.
[0222] In an embodiment, wherein said substituent is unsubstituted
amino. In a further embodiment, the R.sup.9 group is aminomethyl.
In another, the alkyl R.sup.9 group is substituted with
arylcarbonylamino (e.g., heteroarylcarbonylamino, e.g.,
pyridinylcarboynlamino) or alkylcarbonylamino.
[0223] In another further embodiment, the R.sup.9 alkyl group is
substituted with a heterocyclic substituent, such as
isoindole-[1,3]-dione (e.g., phthalimide).
[0224] In an embodiment, R.sup.7 is acyl, e.g., acetyl.
[0225] In yet another embodiment, R.sup.9 is substituted or
unsubstituted alkynyl. The alkynyl R.sup.9 group can be substituted
with any substituent which allows the tetracycline compound of the
invention to perform its intended function. Examples of
substituents include, but are not limited to, alkyl (e.g., methyl,
ethyl, propyl, butyl, pentyl, hexyl, heptyl, etc.), alkenyl,
halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl,
arylcarbonyloxy, arylcarbonylamino, alkoxycarbonylamino,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl,
alkylthio,/sulfate, arylthio, thiocarboxylate, alkylsulfinyl,
sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido,
heterocyclyl, alkylaryl, aryl and heteroaryl.
[0226] In a further embodiment, the aryl substituted alkynyl
R.sup.9 moiety is, for example, substituted or unsubstituted
phenyl. The phenyl may be substituted with, for example, alkoxy,
e.g., methoxy. Examples of alkenyl substituents include
cycloalkenes such as, cyclohexene.
[0227] In one embodiment, R.sup.9 is not unsubstituted phenyl when
R.sup.7 is unsubstituted phenyl.
[0228] Examples of 7,9-substituted 4-dedimethylamino tetracycline
compounds of the invention include those listed below and in Table
2: 363738394041
[0229] The invention also pertains to each of the 4-dedimethylamino
tetracycline compounds shown in Table 2, as well as their
pharmaceutically acceptable salts, esters, and prodrugs.
III. 9-Substituted 4-Dedimethylamino Tetracycline Compounds
[0230] The present invention pertains, at least in part, to novel
9-substituted 4-dedimethylamino tetracycline compounds. These
tetracycline compounds can be used to treat numerous tetracycline
compound-responsive states, such as bacterial infections and
neoplasms, as well as other known applications for tetracycline
compounds, such as blocking tetracycline efflux and modulation of
gene expression.
[0231] The term "9-substituted 4-dedimethylamino tetracycline
compounds" includes tetracycline compounds with substitution at the
9 position. In one embodiment, the substitution at the 9-position
enhances the ability of the tetracycline compound to perform its
intended function, e.g., treat tetracycline responsive states. In
an embodiment, the 9-substituted tetracycline compound is
9-substituted 4-dedimethylamino tetracycline (e.g., wherein R.sup.4
and R.sup.4' are hydrogen, R.sup.5 is hydrogen and X is
CR.sup.6R.sup.6', wherein R.sup.6 is methyl and R.sup.6' is
hydroxy); 9-substituted 4-dedimethylamino doxycycline (e.g.,
wherein R.sup.4 and R.sup.4' are hydrogen, R.sup.5 is hydroxyl and
X is CR.sup.6R.sup.6', wherein R.sup.6 is methyl and R.sup.6' is
hydrogen); 9-substituted dedimethylamino minocycline compounds,
wherein X is CR.sup.6R.sup.6', R.sup.4, R.sup.4', R.sup.5,
R.sup.6', and R.sup.6 are hydrogen, and R.sup.7 is dimethylamino;
or 9-substituted 4-dedimethylamino sancycline (wherein R.sup.4 and
R.sup.4' are hydrogen; R.sup.5 and R.sup.7 are hydrogen and X is
CR.sup.6R.sup.6' wherein R.sup.6 and R.sup.6' are hydrogen
atoms).
[0232] The invention pertains, at least in part, to tetracycline
compounds of Formula IV: 42
[0233] wherein:
[0234] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or
O;
[0235] R.sup.2, R.sup.7' and R.sup.7" are each hydrogen, alkyl,
alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a
prodrug moiety;
[0236] R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, aryl, hydroxyl, alkoxy halogen, hydrogen, or taken
together to form the oxygen of a carbonyl;
[0237] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0238] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0239] R.sup.6 and R.sup.6' are independently hydrogen, methylene,
absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0240] R.sup.7 is NR.sup.7'R.sup.7", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0241] R.sup.9 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a;
[0242] Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O;
[0243] Z' is NR.sup.9f, O or S;
[0244] R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e and
R.sup.9f are each independently hydrogen, acyl, alkyl, alkenyl,
alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a
prodrug moiety;
[0245] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0246] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0247] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts, esters and
prodrugs thereof.
[0248] The term tetracycline compounds refers to compounds of
formula (I) above. In an embodiment, the term minocycline compounds
include compounds wherein X is CR.sup.6R.sup.6'; R.sup.2, R.sup.2',
R.sup.5, R.sup.6, R.sup.6'R.sup.8, R.sup.9, R.sup.10, R.sup.11, and
R.sup.12 are each hydrogen; R.sup.7 is NR.sup.7'R.sup.7"; R.sup.4
and R.sup.4' are each hydrogen or taken together to form the oxygen
of a carbonyl group; and R.sup.7', and R.sup.7" are each lower
alkyl, e.g., methyl.
[0249] Examples of R.sup.9 include substituted and unsubstituted
aryl groups. The aryl groups include substituted and unsubstituted
heteroaryls (e.g., furanyl, imidazolyl, benzothiophenyl,
benzofuranyl, quinolinyl, isoquinolinyl, benzodioxazolyl,
benzoxazolyl, benzothiazolyl, benzoimidazolyl,
methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl,
purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl,
thiazolyl, isothiazolyl, or deazapurinyl), substituted or
unsubstituted phenyl, and groups with more than one aromatic ring,
such as naphthyl.
[0250] Examples of substituents of R.sup.9 include, but are not
limited to, alkyl, alkenyl, halogen, hydroxyl, alkoxy,
alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl,
alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate,
aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido,
imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano,
azido, heterocyclyl, alkylaryl, aryl and heteroaryl.
[0251] In a further embodiment, the aryl R.sup.9 group is
substituted with one or more substituents such as, for example,
carboxylate, alkyl, alkenyl, alkynyl, aryl, heterocyclic, cyano,
amino, halogen, alkoxy, alkoxycarbonyl, amido, alkylcarbonyl, or
nitro.
[0252] In another embodiment, R.sup.9 is substituted or
unsubstituted alkynyl. The alkynyl R.sup.9 group may be substituted
with a substituted or unsubstituted aryl group, such as, for
example, phenyl. The possible substituents for the substituted
phenyl group include, for example, those listed supra, for the aryl
R.sup.9 group. Furthermore, the substituted alkynyl R.sup.9 group
may be substituted with a heteroaryl (e.g, pyridinyl), alkyl (e.g.,
methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, etc.), alkenyl (e.g., ethenyl,
propenyl, butenyl, pentenyl, hexenyl, etc.), carboxylate, silyl
(e.g., trialkylsilyl, e.g., trimethylsilyl), aralkyl, or a
alkyloxycarbonyl group.
[0253] Each of these groups may also be further substituted, with
such substituents as alkyl, alkenyl, halogen, hydroxyl, alkoxy,
alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl.
[0254] In a further embodiment, the alkynyl R.sup.9 group is
substituted with an aminoalkyl group. The aminoalkyl group may then
also be substituted with, for example, an alkyl, alkenyl, alkynyl,
acyl, carbonyl, or alkylsulfone group.
[0255] In another further embodiment, the alkynyl R.sup.9 group is
substituted with a cycloalkenyl group, such as, for example,
cyclopentene.
[0256] In another embodiment, R.sup.9 is alkyl. The alkyl group may
be substituted or unsubstituted. Examples of alkyl groups include,
for example, both straight chain, branched and cyclic alkyl groups.
For example, alkyl groups include methyl, ethyl, i-propyl,
n-propyl, i-butyl, n-butyl, t-butyl, pentyl, hexyl, heptyl, octyl,
nonyl, decyl, etc. Cyclic alkyl groups include groups with one or
more rings, such as, for example, cyclopropane, cyclobutane,
cyclopentane, cyclohexane, cycloheptane, etc. In an embodiment, the
alkyl R.sup.9 group is 2-cyclopentylethyl.
[0257] Examples of substituents of alkyl groups include, for
example, halogens (e.g., fluorine, chlorine, bromine, iodine,
etc.), hydroxyl, alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy,
pentoxy, perfluoromethoxy, perchloromethoxy, etc.),
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
carboxy, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano,
amino, acylamino, amido, imino, sulfhydryl, alkylthio, arylthio,
thiocarboxylate, sulfate, alkylsulfinyl, alkenyl, sulfonato,
sulfamoyl, sulfonamido, nitro, alkenyl, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl.
[0258] In another embodiment, the minocycline compound of the
invention is a compound wherein R.sup.9 is
--NR.sup.9cC(=Z')ZR.sup.9a, --CH.sub.2NR.sup.9cC(=Z')ZR.sup.9a,
--(CH.sub.2).sub.2NR.sup.9cC(=Z')ZR.s- up.9a, or
--(CH.sub.2).sub.3NR.sup.9cC(=Z')ZR.sup.9a. In certain embodiments,
R.sup.9 is --NR.sup.9cC(=Z')ZR.sup.9a or
--CH.sub.2NR.sup.9cC(=Z')ZR.sup.9a. Examples of R.sup.9c include
hydrogen. Z' may be, for example, S, NH, or O. Examples of Z
include NR.sup.9b (e.g., when R.sup.9b is hydrogen, alkyl, etc.), O
or S.
[0259] Examples of R.sup.9a groups include aryl groups such as
substituted and unsubstituted phenyl. Examples of possible
substituents of aryl R.sup.9a groups include, but are not limited
to, alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl,
perfluormethyl, perchloroethyl, etc.), alkenyl, halogen (e.g.,
fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy (e.g,
methoxy, ethoxy, propoxy, perfluoromethoxy, perchloromethoxy,
etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl,
alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate,
phosphonato, phosphinato, cyano, amino, acylamino, amido, imino,
sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, acetyl,
alkyl, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl
groups.
[0260] In certain embodiments, at least one of the substituents of
the substituted phenyl is nitro, alkoxy (e.g., methoxy,
methylenedioxy, perfluoromethoxy) alkyl (e.g., methyl, ethyl,
propyl, butyl, or pentyl), acetyl, halogen (e.g., fluorine,
chlorine, bromine, or iodine), or amino (e.g., dialkylamino). In
certain embodiments, the alkoxy group is perhalogenated, e.g.,
perfluoromethoxy.
[0261] Examples of aryl R.sup.9a groups include, but are not
limited to, unsubstituted phenyl, para-nitrophenyl, para-methoxy
phenyl, para-perfluoromethoxy phenyl, para-acetyl phenyl,
3,5-methylenedioxypheny- l, 3,5-diperfluoromethyl phenyl,
para-bromo phenyl, para-chloro phenyl, and para-fluoro phenyl.
[0262] Other examples of aryl R.sup.9a groups include substituted
and unsubstituted heterocycles (e.g., furanyl, imidazolyl,
benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl,
benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl,
methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl,
purinyl, pyrazolyl, pyrolidinyl, oxazolyl, isooxazolyl,
naphthridinyl, thiazolyl, isothiazolyl, or deazapurinyl) and
substituted and unsubstituted biaryl groups, such as naphthyl and
fluorene.
[0263] R.sup.9a also may be substituted or unsubstituted alkyl,
e.g., methyl, ethyl, propyl, butyl, pentyl, etc. Examples of
substituents include but are not limited to halogens (e.g.,
fluorine, bromine, chlorine, iodine, etc.), hydroxyl, alkoxy (e.g.,
methoxy, ethoxy, propoxy, butoxy, etc.), alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl
aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,
arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl,
aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato,
phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl,
alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl,
sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano,
azido, alkenyl, heterocyclyl, alkylaryl, aryl and heteroaryl.
[0264] R.sup.9a also can be substituted or unsubstituted alkenyl.
Examples of substituents for alkenyl R.sup.9a groups include those
listed above for alkyl R.sup.9a groups. Examples of alkenyl
R.sup.9a groups include pent-1-enyl.
[0265] In an embodiment, Z' is NH, Z is NH, and R.sup.9a is
alkyl.
[0266] The invention also pertains to compounds wherein R.sup.9 is
aminoalkyl (e.g., aminomethyl). Aminoalkyl R.sup.9 groups may be
further substituted. Examples of substituents include aryl groups,
such as, for example substituted or unsubstituted phenyl (e.g.,
methylenedioxyphenyl or para-perfluoromethoxyphenyl), or
heteroaromatic groups which allows the compound of the invention to
perform its intended function.
[0267] Examples of tetracycline compounds of the invention include
those listed in Table 2, as well as the ones listed below:
4344454647
[0268] Pharmaceutically acceptable salts of these compounds are
also included. Other compound of the invention are listed in Table
2.
[0269] The invention also relates, at least in part, to
9-substituted 4-dedimethyl amino minocycline compounds of the
formula: 48
[0270] wherein:
[0271] R.sup.7', and R.sup.7" are each alkyl; and
[0272] R.sup.9 is a pyridylethynyl group; an alkenylcarbamate
group; a halo group; an alkylacrylate group; a naphthyl urea group;
a haloacetyl group; an alkyl carbamate group; a cyclopentyl or
cyclopentenyl group; a benzofuranyl group; a phenylpropiononeamino
group; a tosylamino group; a methoxypyridyl group; an alkeneamino
group; an N-t-butyl group; a t-butylamide group; a
hydroxybutylamino group; a hydroxypropylamino group; a phenyl
group; a nitrophenyl group; a nitrophenyl alkynyl group; an
aminophenyl group; a halophenyl urea group; an alkoxyphenyl group;
a cyanophenyl group; a carboxyphenyl group; an acylphenyl group; an
alkylphenyl group; a halophenyl group; an alkoxyphenyl group; a
carboxyalkylphenyl group; a phenylalkynyl group; an alkynyl group;
an alkylglycineethylester group; a styrene group; a thiophene
group; an alkylaminophospho group; and pharmaceutically acceptable
salts thereof.
[0273] The term "9-substituted 4-dedimethylamino minocycline
compound" includes minocycline compounds with a substituent at the
9 position and a substituent other than dimethylamino at the 4
position. In another embodiment, the compound is a derivative of
minocycline.
[0274] In an embodiment, R.sup.9 is an alkenylcarbamate group.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-isopropenyl carbamate 4-dedimethylamino minocycline.
[0275] In an embodiment, R.sup.9 is a pyridylethynyl group.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-(2-pyridylethynyl) 4-dedimethylamino minocycline.
[0276] In an embodiment, R.sup.9 is a halo group. Examples of
minocycline compounds with this R.sup.9 substituent include 9-iodo
4-dedimethylamino minocycline.
[0277] In an embodiment, R.sup.9 is an alkylacrylate group.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-butylacrylate 4-dedimethylamino minocycline.
[0278] In an embodiment, R.sup.9 is a naphthyl urea group. Examples
of minocycline compounds with this R.sup.9substituent include
9-naphthyl 4-dedimethylamino minocycline urea.
[0279] In an embodiment, R.sup.9 is a haloacetyl group. Examples of
minocycline compounds with this R.sup.9 substituent include
9-chloroacetyl 4-dedimethylamino minocycline urea.
[0280] In an embodiment, R.sup.9 is an alkyl carbamate group.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-neopentyl 4-dedimethylamino minocycline carbamate.
[0281] In an embodiment, R.sup.9 is a cyclopentyl or cyclopentenyl
group. Examples of minocycline compounds with this R.sup.9
substituent include 9-cyclopentene 4-dedimethylamino
minocycline.
[0282] In an embodiment, R.sup.9 is a benzofuranyl group. Examples
of minocycline compounds with this R.sup.5 substituent include
9-benzofuranyl 4-dedimethylamino minocycline.
[0283] In an embodiment, R.sup.9 is a phenylpropiononeamino group.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-(phenylpropiononeamino) 4-dedimethylamino
minocycline.
[0284] In an embodiment, R.sup.9 is a tosylamino group. Examples of
minocycline compounds with this R.sup.9 substituent include
9-tosylamino 4-dedimethylamino minocycline.
[0285] In an embodiment, R.sup.9 is a methoxypyridyl group.
Examples of minocycline compounds with this R.sup.5 substituent
include 9-(2-methoxy-3-pyridyl) 4-dedimethylamino minocycline.
[0286] In an embodiment, R.sup.5 is an alkeneamino group. Examples
of minocycline compounds with this R.sup.9 substituent include
9-(N-2'-hydroxydecyl-9'-ene-amino) 4-dedimethylamino
minocycline.
[0287] In an embodiment, R.sup.9 is an N-t-butyl group. Examples of
minocycline compounds with this R.sup.9 substituent include
N-t-butyl-4-dedimethylamino minocycline HCl.
[0288] In an embodiment, R.sup.9 is a t-butylamide group. Examples
of minocycline compounds with this R.sup.9 substituent include
9-BOC-NH 4-dedimethylamino minocycline.
[0289] In an embodiment, R.sup.9 is a hydroxybutylamino group.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-(N-2'-hydroxybutylamino) 4-dedimethylamino
minocycline.
[0290] In an embodiment, R.sup.9 is a hydroxypropylamino group.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-(N-3-chloro, 2-hydroxylpropylamino) 4-dedimethylamino
minocycline.
[0291] In an embodiment, R.sup.9 is a phenyl group. Examples of
minocycline compounds with this R.sup.9 substituent include
9-phenyl 4-dedimethylamino minocycline HCl and 9-p-tolyl
4-dedimethylamino minocycline.
[0292] In an embodiment, R.sup.9 is a nitrophenyl group. Examples
of minocycline compounds with this R.sup.9 substituent include
9-(3'-nitrophenyl) 4-dedimethylamino minocycline.
[0293] In an embodiment, R.sup.9 is a nitrophenyl alkynyl group.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-(4'-nitrophenylethynyl) 4-dedimethylamino
minocycline.
[0294] In an embodiment, R.sup.9 is an aminophenyl group. Examples
of minocycline compounds with this R.sup.9 substituent include
9-(3-aminophenyl) 4-dedimethylamino minocycline.
[0295] In an embodiment, R.sup.9 is a halophenyl urea group;.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-(4-chloro,2-trifluoromethylphenyl) 4-dedimethylamino
minocycline urea.
[0296] In an embodiment, R.sup.9 is an alkoxyphenyl group. Examples
of minocycline compounds with this R.sup.9 substituent include
9-(p-methoxyphenyl) 4-dedimethylamino minocycline,
9-(4'-methoxyphenyl) 4-dedimethylamino minocycline, and
9-(3,4-methylenedioxyphenyl) 4-dedimethylamino minocycline.
[0297] In an embodiment, R.sup.9 is a cyanophenyl group. Examples
of minocycline compounds with this R.sup.9 substituent include
9-(4'-cyanophenyl) 4-dedimethylamino minocycline.
[0298] In an embodiment, R.sup.9 is a carboxyalkylphenyl group.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-(4'-carboxyphenyl) 4-dedimethylamino minocycline.
[0299] In an embodiment, R.sup.9 is an acylphenyl group. Examples
of minocycline compounds with this R.sup.9 substituent include
9-(3-formylphenyl) 4-dedimethylamino minocycline.
[0300] In an embodiment, R.sup.9 is an alkylphenyl group. Examples
of minocycline compounds with this R.sup.9 substituent include
9-(4'-t-butylphenyl) 4-dedimethylamino minocycline.
[0301] In an embodiment, R.sup.9 is a halophenyl group. Examples of
minocycline compounds with this R.sup.9 substituent include
9-(3-chlorophenyl) 4-dedimethylamino minocycline,
9-(2',4'-difluorophenyl- ) 4-dedimethylamino minocycline,
9-(3,4-difluorophenyl) 4-dedimethylamino minocycline,
9-(4'-chlorophenyl) 4-dedimethylamino minocycline,
9-(3,4-dichlorophenyl) 4-dedimethylamino minocycline, and
9-(4'-trifluoromethylphenyl) 4-dedimethylamino minocycline.
[0302] In an embodiment, R.sup.9 is an alkoxyphenyl group. Examples
of minocycline compounds with this R.sup.9 substituent include
9-(3-ethoxyphenyl) 4-dedimethylamino minocycline.
[0303] In an embodiment, R.sup.9 is a carboxyalkylphenyl group.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-(4-carboxymethylphenyl) 4-dedimethylamino
minocycline.
[0304] In an embodiment, R.sup.9 is a phenylalkynyl group. Examples
of minocycline compounds with this R.sup.9 substituent include
9-(phenylethynyl) 4-dedimethylamino minocycline,
9-(3-hydroxyphenylethyny- l) 4-dedimethylamino minocycline,
9-(p-tolylethynyl) 4-dedimethylamino minocycline, and
9-(p-methoxyphenylethynyl) 4-dedimethylamino minocycline.
[0305] In an embodiment, R.sup.9 is an alkynyl group. Examples of
minocycline compounds with this R.sup.9 substituent include
9-ethynyl 4-dedimethylamino minocycline, 9-(p-fluoroethynyl)
4-dedimethylamino minocycline, 9-(trimethylsilylethynyl)
4-dedimethylamino minocycline, 9-(propionyl) 4-dedimethylamino
minocycline, 9-(cyclohexenylethynyl) 4-dedimethylamino minocycline,
and 9-(1-cyclohexyl-1-hydroxyethynyl) 4-dedimethylamino
minocycline.
[0306] In an embodiment, R.sup.9 is an alkylglycineethylester
group. Examples of minocycline compounds with this R.sup.9
substituent include 9-propylglycineethylester 4-dedimethylamino
minocycline HCl, and 9-methylglycineethylester 4-dedimethylamino
minocycline.
[0307] In an embodiment, R.sup.9 is a styrene group. Examples of
minocycline compounds with this R.sup.9 substituent include
9-(styrene) 4-dedimethylamino minocycline, 9-(4'-fluorostyrene)
4-dedimethylamino minocycline.
[0308] In an embodiment, R.sup.9 is a thiophene group. Examples of
minocycline compounds with this R.sup.9 substituent include
9-(2-thiophene) 4-dedimethylamino minocycline, and
9-(5'-chloro-2'-thiophene) 4-dedimethylamino minocycline.
[0309] In an embodiment, R.sup.9 is an alkylaminophospho group.
Examples of minocycline compounds with this R.sup.9 substituent
include 9-(p-methoxyphenylaminophospho) 4-dedimethylamino
minocycline, and 9-(phenylaminophospho) 4-dedimethylamino
minocycline.
IV. 13-Substituted 4-Dedimethylamino Tetracycline Compounds
[0310] The invention pertains to 13-substituted 4-dedimethylamino
tetracycline compounds of the formula: 49
[0311] wherein:
[0312] R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, hydroxyl, halogen, hydrogen, or when taken together the
oxygen of a carbonyl group;
[0313] R.sup.5 is hydrogen, hydroxyl, or a prodrug moiety;
[0314] R.sup.6 is an alkyl or an aryl group, and pharmaceutically
acceptable salts, esters, and prodrugs thereof.
[0315] The term "13-substituted 4-dedimethylamino tetracycline
compounds" includes 4-dedimethylamino methacycline compounds with a
substituent at the 13 position (e.g., a compound of formula I with
a substituent at the R.sup.6 position). In an embodiment, the
13-substituted 4-dedimethylamino methacycline compound is
13-substituted 4-dedimethylamino methacycline (e.g., wherein
R.sup.4 and R.sup.4' are hydrogen, and R.sup.5 is hydroxyl). In
another embodiment, R.sup.4 and R.sup.4' taken together are the
oxygen of a carbonyl group.
[0316] In a further embodiment, R.sup.6 is a phenyl group, i.e., an
alkoxyphenyl group, a halophenyl group, a carboxyphenyl group, an
acylphenyl group, a cyanophenyl group, a nitrophenyl group, a
naphthyl group, a dialkylphenyl group, or an alkylphenyl group; a
t-butyl group; or an aminoalkanethio group.
[0317] In yet another embodiment, R.sup.6 is a phenyl group, i.e.,
an alkoxyphenyl group, an halophenyl group, a carboxyphenyl group,
an acylphenyl group, a cyanophenyl group, a nitrophenyl group, a
naphthyl group or an alkylphenyl group; a t-butyl group; an
aminoalkanethio group. Examples of compounds where R.sup.6 is a
phenyl group include 13-(phenyl) 4-dedimethylamino methacycline and
13-(4'-chlorophenyl-5-cyclohexanoate) 4-dedimethylamino
methacycline.
[0318] In an embodiment, R.sup.6 is an alkoxyphenyl group. Examples
of such compounds include 13-(4'-methoxyphenyl) 4-dedimethylamino
methacycline, 13-(methylenedioxyphenyl) 4-dedimethylamino
methacycline, 13-(4'-ethoxyphenyl) 4-dedimethylamino methacycline,
13-(p-carbomethoxyphenyl) 4-dedimethylamino methacycline, and
13-(3',4'-methylenedioxyphenyl) 4-dedimethylamino methacycline.
[0319] In an embodiment, R.sup.6 is a halophenyl group. Examples of
such compounds include 13-(4'-fluorophenyl) 4-dedimethylamino
methacycline, 13-(4'-chlorophenyl) 4-dedimethylamino methacycline,
13-(3'-chlorophenyl) 4-dedimethylamino methacycline,
13-(methylenedioxyphenyl) 4-dedimethylamino methacycline,
13-(3'-carboxylphenyl) 4-dedimethylamino methacycline,
13-(3'-4'-dichlorophenyl) 4-dedimethylamino methacycline,
13-(4'-acetylphenyl) 4-dedimethylamino methacycline,
13-(4'-ethoxyphenyl) 4-dedimethylamino methacycline,
13-(4'-chlorophenyl-5-cyclohexanoate) 4-dedimethylamino
methacycline, 13-(3,5-difluorophenyl) 4-dedimethylamino
methacycline, 13 -(3'-acetylphenyl) 4-dedimethylamino methacycline,
13-(4'-bromophenyl) 4-dedimethylamino methacycline,
13-(2,4-difluorophenyl) 4-dedimethylamino methacycline,
13-(2-chlorophenyl) 4-dedimethylamino methacycline,
13-(p-carbomethoxyphenyl) 4-dedimethylamino methacycline, and
13-(trifluoromethylphenyl) 4-dedimethylamino methacycline.
[0320] In an embodiment, R.sup.6 is a carboxyphenyl group. Examples
of such compounds include 13-(3'-carboxylphenyl) 4-dedimethylamino
methacycline.
[0321] In an embodiment, R.sup.6 is an acylphenyl group. Examples
of such compounds include 13-(3'-acetylphenyl) 4-dedimethylamino
methacycline, 13-(4'-acetylphenyl) 4-dedimethylamino methacycline,
and 13-(3'-formyl) 4-dedimethylamino methacycline.
[0322] In an embodiment, R.sup.6 is a cyanophenyl group. Examples
of such compounds include 13-(p-cyanophenyl) 4-dedimethylamino
methacycline.
[0323] In an embodiment, R.sup.6 is a nitrophenyl group. Examples
of such compounds include 13-(4'-nitrophenyl) 4-dedimethylamino
methacycline.
[0324] In an embodiment, R.sup.6 is a naphthyl group. Examples of
such compounds include 13-(naphthyl) 4-dedimethylamino
methacycline.
[0325] In an embodiment, R.sup.6 is an dialkylphenyl group.
Examples of such compounds include 13-(3,5-dimethylphenyl)
4-dedimethylamino methacycline.
[0326] In an embodiment, R.sup.6 is an alkylphenyl group. Examples
of such compounds include 13-(p-t-butylphenyl) 4-dedimethylamino
methacycline and 13-(p-tolyl) 4-dedimethylamino methacycline.
[0327] In an embodiment, R.sup.6 is a t-butyl group. Examples of
such compounds include 9,13-di-t-butyl) 4-dedimethylamino
methacycline.
[0328] In an embodiment, R.sup.6 is an aminoalkanethio group.
Examples of such compounds include 13-(dimethylaminoethanethio)
4-dedimethylamino methacycline.
[0329] Examples of 13-substituted methacycline compounds include
13-(phenyl) 4-dedimethylamino methacycline,
13-(4'-chlorophenyl-5-cyclohe- xanoate) 4-dedimethylamino
methacycline, 13-(4'-methoxyphenyl) 4-dedimethylamino methacycline,
13-(methylenedioxyphenyl) 4-dedimethylamino methacycline,
13-(4'-ethoxyphenyl) 4-dedimethylamino methacycline,
13-(p-carbomethoxyphenyl) 4-dedimethylamino methacycline,
13-(3',4'-methylenedioxyphenyl) 4-dedimethylamino methacycline, 13
-(4'-fluorophenyl) 4-dedimethylamino methacycline, 13
-(4'-chlorophenyl) 4-dedimethylamino methacycline,
13-(3'-chlorophenyl) 4-dedimethylamino methacycline,
13-(methylenedioxyphenyl) 4-dedimethylamino methacycline,
13-(3'-carboxylphenyl) 4-dedimethylamino mnethacycline,
13-(3'-4'-dichlorophenyl) 4-dedimethylamino methacycline,
13-(4'-acetylphenyl) 4-dedimethylamino methacycline,
13-(4'-ethoxyphenyl) 4-dedimethylamino methacycline,
13-(4'-chlorophenyl-5-cyclohexanoate) 4-dedimethylamino
methacycline, 13-(3,5-difluorophenyl) 4-dedimethylamino
methacycline, 13-(3'-acetylphenyl) 4-dedimethylamino methacycline,
13-(4'-bromophenyl) 4-dedimethylamino methacycline,
13-(2,4-difluorophenyl) 4-dedimethylamino methacycline,
13-(2-chlorophenyl) 4-dedimethylamino methacycline,
13-(p-carbomethoxyphenyl) 4-dedimethylamino methacycline,
13-(trifluoromethylphenyl) 4-dedimethylamino methacycline,
13-(3'-carboxylphenyl) 4-dedimethylamino methacycline,
13-(3'-acetylphenyl) 4-dedimethylamino methacycline,
13-(4'-acetylphenyl) 4-dedimethylamino methacycline, 13-(3'-formyl)
4-dedimethylamino methacycline, 13-(p-cyanophenyl)
4-dedimethylamino methacycline, 13-(4'-nitrophenyl)
4-dedimethylamino methacycline, 13-(naphthyl) 4-dedimethylamino
methacycline, 13-(p-t-butylphenyl) 4-dedimethylamino methacycline,
13-((3,5-dimethylphenyl) 4-dedimethylamino methacycline,
13-(p-tolyl) 4-dedimethylamino methacycline, 9,13-(di-t-butyl)
4-dedimethylamino methacycline, 13-(dimethylaminoethanethio)
4-dedimethylamino methacycline, and pharmaceutically acceptable
esters, prodrugs, and salts thereof.
[0330] Other examples of compounds include: 5051525354
[0331] and pharmaceutically acceptable esters, salts, and prodrugs
thereof.
VI. 8-Substituted 4-Dedimethylamino Tetracycline Compounds
[0332] The term "8-substituted 4-dedimethylamino tetracycline
compounds" includes tetracycline compounds with a substituent at
the 8 position, as described in formula I, and a substituent other
than dimethylamino at the 8 position. In an embodiment, the
substituted tetracycline compound is a substituted
4-dedimethylamino doxycycline derivative (e.g., wherein R.sup.4 and
R.sup.4' are hydrogen, R.sup.5 is hydroxyl, R.sup.6 is methyl, and
R.sup.6' is hydrogen).
[0333] In an embodiment, the invention pertains, at least in part,
to 8-substituted 4-dedimethylamino tetracycline compound of formula
VII: 55
[0334] wherein:
[0335] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6,
C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
[0336] R.sup.2 and R.sup.2' are each independently hydrogen, alkyl,
alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a
prodrug moiety;
[0337] R.sup.4 and R.sup.4' are each independently alkyl, alkenyl,
alkynyl, hydroxyl, halogen, hydrogen, or when taken together the
oxygen of a carbonyl group;
[0338] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0339] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0340] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0341] R.sup.7 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, or --(CH.sub.2).sub.0-3NR.sup.7cC(.dbd.W
')WR.sup.7a;
[0342] R.sup.9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, thionitroso(e.g., --N.dbd.S), or
--(CH.sub.2).sub.0-3NR.sup.- 9cC(=Z')ZR.sup.9a;
[0343] Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O;
[0344] Z' is O, S, or NR.sup.9f;
[0345] W is CR.sup.7dR.sup.7e, S, NR.sup.7b or O;
[0346] W' is O, NR.sup.7fS;
[0347] R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.9a,
R.sup.9b, R.sup.9c, R.sup.9d, and R.sup.9e are each independently
hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0348] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0349] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0350] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts, prodrugs and
esters thereof.
[0351] In an embodiment, X is CR.sup.6R.sup.6'; R.sup.2, R.sup.2',
R.sup.6, R.sup.6', R.sup.8, R.sup.9, R.sup.10, R.sup.11, and
R.sup.12 are each hydrogen; R.sup.4 and R.sup.4' are hydrogen,
halogen (e.g., chlorine, fluorine, bromine, iodine, etc.), hydroxy,
or when taken together the oxygen of a carbonyl group; and R.sup.5
is bydroxy or hydrogen. In a further embodiment, R.sup.4, R.sup.4',
and R.sup.5 are each hydrogen; R.sup.7 is hydrogen; and R.sup.9 is
hydrogen or amino.
[0352] In another embodiment, R.sup.8 is halogen, alkyl, alkenyl,
alkynyl, aryl or heteroaryl. R.sup.8 may be further substituted or
unsubstituted.
[0353] In a further embodiment, R.sup.8 is aryl. Examples of aryl
R.sup.8 groups include substituted or unsubstituted phenyl. The
phenyl R.sup.8 group can be substituted with any substituent which
allow the tetracycline compound to perform its intended function.
Examples of substituents include, but are not limited to, alkyl,
alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,
alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl.
[0354] The aryl R.sup.8 group also may be heteroaryl. Examples of
heteroaryl R.sup.8 moieties include, but are not limited to,
furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl,
isoquinolinyl, pyridinyl, pyrazolyl, benzodioxazolyl, benzoxazolyl,
benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl,
thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl,
isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, and
deazapurinyl. In certain embodiments, the heteroaryl R.sup.7 group
is thiazolyl, thiophenyl, or furanyl.
[0355] R.sup.8 also may be substituted or unsubstituted alkyl. The
alkyl group can be a straight or branched chain, e.g., methyl,
ethyl, i-propyl, n-propyl, n-butyl, i-butyl, t-butyl, pentyl,
hexyl. etc. The alkyl group may also comprise a ring, e.g., a
cycloalkyl (e.g., cyclopentyl, cyclohexyl, cyclopropyl, or
cyclobutyl). The alkyl R.sup.8 group may be substituted with any
substituent or combination of substituents which allows the
compound to perform its intended function. Examples of substituents
include, but are not limited to, alkenyl, halogen, hydroxyl,
alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy,
arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl.
[0356] R.sup.8 also may be substituted or unsubstituted alkenyl.
Examples of substituents include those which allow the compound to
perform its intended function. Examples of substituents include but
are not limited to alkyl, halogen, hydroxyl, alkoxy,
alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy,
alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl
aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,
aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl,
silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl,
phosphonato, phosphinato, cyano, amino, acylamino, amido, imino,
sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano,
azido, heterocyclyl, alkylaryl, aryl and heteroaryl moieties.
[0357] Another example of R.sup.8 include substituted and
unsubstituted alkynyls. The alkynyl moieties can be substituted
with any substituent or combination of substituents which allow the
tetracycline compound of the invention to perform its intended
function. Examples of the substituents include, but are not limited
to alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,
alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl,
alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato,
cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio,
sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl,
alkylaryl, aryl and heteroaryl moieties.
[0358] The invention pertains to, at least in part, to
8-substituted tetracycline compounds of the formula (VIII): 56
[0359] wherein:
[0360] R.sup.5 is hydrogen or hydroxyl;
[0361] R.sup.6 and R.sup.6' are each independently hydrogen,
methyl, or hydroxyl;
[0362] R.sup.7 is hydrogen,
[0363] R.sup.8 is phenyl, nitrophenyl, halo, or lower alkynyl;
and
[0364] R.sup.9 is hydrogen or amino, and pharmaceutically
acceptable salts, prodrugs and esters thereof.
[0365] In an embodiment, doxycycline derivatives of tetracycline
compounds of the invention include compounds wherein R.sup.7 is
hydrogen, R.sup.8 is halo, phenyl, or nitrophenyl, and R.sup.9 is
hydrogen. In an alternate embodiment, R.sup.7 is hydrogen, R.sup.8
is phenyl or lower alkynyl (e.g., ethynyl), and R.sup.9 is
amino.
[0366] Examples of such tetracycline compounds which are
doxycycline derivatives include 8-phenyl 4-dedimethylamino
doxycycline, 8-bromo 4-dedimethylamino doxycycline,
8-(p-nitrophenyl) 4-dedimethylamino doxycycline, 8-ethynyl-9-amino
4-dedimethylamino doxycycline, and 8-phenyl-9-amino
4-dedimethylamino doxycycline.
[0367] Other compounds of the invention are shown in Table 2,
below.
2TABLE 2 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97
98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114
115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131
132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148
149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165
166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182
183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199
200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216
217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233
234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250
251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267
268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284
285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301
302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318
319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335
336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352
353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369
370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386
387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403
404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420
421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437
438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454
455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471
472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488
489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505
506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522
523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539
540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556
557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573
574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590
591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607
608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624
625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641
642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658
659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675
676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692
693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709
710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726
727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743
744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760
761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777
778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794
795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811
812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828
829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845
846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862
863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879
880 881 882 883 884 885 886 887 888 889 890 891
[0368]
3 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907
908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924
925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941
942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958
959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975
976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992
993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007
1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020
1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033
1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046
1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059
1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072
1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085
1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098
1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111
1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124
1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137
1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150
1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163
1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176
1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189
1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202
1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215
1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228
1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241
1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254
1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267
1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280
1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293
1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306
1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319
1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332
1333 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345
1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357 1358
1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371
1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384
1385 1386 1387 1388 1389 1390 1391 1392 1393 1394 1395 1396 1397
1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410
1411 1412 1413 1414 1415 1416 1417 1418 1419 1420 1421 1422 1423
1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436
1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449
1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462
1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475
1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488
1489 1490 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 1501
1502 1503 1504 1505 1506 1507 1508 1509 1510 1511 1512 1513 1514
1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527
1528 1529 1530 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540
1541 1542 1543 1544 1545 1546 1547 1548 1549 1550 1551 1552 1553
1554 1555 1556 1557 1558 1559 1560 1561 1562 1563 1564 1565 1566
1567 1568 1569 1570 1571 1572 1573 1574 1575 1576 1577 1578 1579
1580 1581 1582 1583 1584 1585 1586 1587 1588 1589 1590 1591 1592
1593 1594 1595 1596 1597 1598 1599 1600 1601 1602 1603 1604 1605
1606 1607 1608 1609 1610 1611 1612 1613 1614 1615 1616 1617 1618
1619 1620 1621 1622 1623 1624 1625 1626 1627 1628 1629 1630 1631
1632 1633 1634 1635 1636 1637 1638 1639 1640 1641 1642 1643 1644
1645 1646 1647 1648 1649 1650 1651 1652 1653 1654 1655 1656 1657
1658 1659 1660 1661 1662 1663 1664 1665 1666 1667 1668 1669 1670
1671 1672 1673 1674 1675 1676 1677 1678 1679 1680 1681 1682 1683
1684 1685 1686 1687 1688 1689 1690 1691 1692 1693 1694 1695 1696
1697 1698 1699 1700 1701 1702 1703 1704 1705 1706 1707 1708
1709
VI. Synthetic Methods for the Synthesis of Tetracycline
Compounds
[0369] The tetracycline compounds of this invention can be
synthesized using the methods described in the Schemes and Examples
below.
[0370] Certain substituted 4-dedimethylamino tetracycline compounds
can be synthesized by the method shown in Scheme 1. Although in
each scheme sancycline is used as the tetracycline compound, one of
skill in the art will appreciate that the methodology can also be
applied to other tetracycline compounds such as tetracycline and
doxycycline. In addition, similar methodology can be used to
synthesize 9-substituted 4-dedimethylamino tetracycline compounds.
1710
[0371] Generally, substituted 4-dedimethylamino tetracycline
compounds can be synthesized as shown in Scheme 1 for
4-dedimethylamino sancycline. 4-Dedimethylamino sancycline (1A) is
treated with sulfuric acid and sodium nitrate. The resulting
product is 7-nitro (1B) 4-dedimethylamino sancycline (in a mixture
with the 9-position isomers). The nitro 4-dedimethylamino
sancycline compound is then treated with hydrogen gas and a
platinum catalyst to yield the 7-amino 4-dedimethylamino sancycline
compound, 1C. To synthesize 7 derivatives, the 7-amino
4-dedimethylamino sancycline compound is treated with HONO, to
yield the diazonium salt (1D). The salt can subsequently be treated
with numerous compounds possessing an alkene or n bond functional
group such as alkenes, aryls, and alkynyls (e.g., R.sup.7Br)
yielding the 7-substituted sancycline compound (1E). 1711
[0372] As shown in Scheme 2, 4-dedimethylamino tetracycline
compounds of the invention wherein R.sup.7 is a carbamate or a urea
derivative can be synthesized using the following protocol.
4-Dedimethylamino sancycline (2A) is treated with NaNO.sub.2 under
acidic conditions forming 7-nitro 4-dedimethylamino sancycline (2B)
in a mixture of positional isomers. 7-nitro 4-dedimethylamino
sancycline (2B) is then treated with H.sub.2 gas and a platinum
catalyst to form the 7-amino 4-dedimethylamino sancycline
derivative (2C). To form the urea derivative (2E), isocyanate (2D)
is reacted with the 7-amino sancycline derivative (2C). To form the
carbamate (2G), the appropriate acid chloride ester (2F) is reacted
with 2C. 1712
[0373] As shown in Scheme 3, 4-dedimethylamino tetracycline
compounds of the invention, wherein R.sup.7 is a heterocyclic (i.e.
thiazole) substituted amino group can be synthesized using the
above protocol. 7-amino 4-dedimethylamino sancycline (3A) is
reacted with Fmoc-isothiocyanate (3B) to produce the protected
thiourea (3C). The protected thiourea (3C) is then deprotected
yielding the active 4-dedimethylamino sancycline thiourea (3D)
compound. The 4-dedimethylamino sancycline thiourea (3D) is reacted
with an .alpha.-haloketone (3E) to produce a thiazole substituted
7-amino 4-dedimethylamino sancycline (3F). 1713
[0374] Alkenyl substituted 4-dedimethylamino tetracycline
compounds, such as 7-alkynyl 4-dedimethylamino sancycline (4A) and
7-alkenyl 4-dedimethylamino sancycline (4B), can be hydrogenated to
form alkyl substituted 4-dedimethylamino tetracycline compounds
(e.g., 7-alkyl 4-dedimethylamino sancycline, 4C). Scheme 4 depicts
the selective hydrogenation of the 7-position double or triple
bond, in saturated methanol and hydrochloric acid solution with a
palladium/carbon catalyst under pressure, to yield the product. A
9-position double or triple bond can be treated in a similar
manner. 1714
[0375] In Scheme 5, a general synthetic scheme for synthesizing
7-position aryl derivatives is shown. Similar methodology can be
used to synthesize 9-position aryl derivatives. A Suzuki coupling
of an aryl boronic acid with an iodosancycline compound is shown.
An iodo 4-dedimethylamino sancycline compound (5B) can be
synthesized from 4-dedimethylamino sancycline by treating
4-dedimethylamino sancycline (5A) with at least one equivalent
N-iodosuccinimide (NIS) under acidic conditions. The reaction is
quenched, and the resulting 7-iodo 4-dedimethylamino sancycline
(5B) can then be purified using standard techniques known in the
art. To form the aryl derivative, 7-iodo 4-dedimethylamino
sancycline (5B) is treated with an aqueous base (e.g.,
Na.sub.2CO.sub.3) and an appropriate boronic acid (5C) and under an
inert atmosphere. The reaction is catalyzed with a palladium
catalyst (e.g., Pd(OAc).sub.2). The product (5D) can be purified by
methods known in the art (such as HPLC). Other 7-aryl and alkynyl
tetracycline compounds can be synthesized using similar
protocols.
[0376] The substituted 4-dedimethylamino tetracycline compounds of
the invention can also be synthesized using Stille cross couplings.
Stille cross couplings can be performed using an appropriate tin
reagent (e.g., R--SnBu.sub.3) and a halogenated 4-dedimethylamino
tetracycline compound, (e.g., 7-iodo 4-dedimethylamino sancycline).
The tin reagent and the iodo 4-dedimethylamino sancycline compound
can be treated with a palladium catalyst (e.g.,
Pd(PPh.sub.3).sub.2Cl.sub.2 or Pd(AsPh.sub.3).sub.2Cl.sub- .2) and,
optionally, with an additional copper salt, e.g., CuI. The
resulting compound can then be purified using techniques known in
the art. 1715
[0377] The aryl derivatives formed by Suzuki or Stille couplings,
can be further derivitized. For example in Scheme 6, a formyl aryl
4-dedimethylamino sancycline (6A), an amine, and a solvent (e.g.,
1,2 dichloroethane) are combined in a reaction flask. A reducing
agent is then added (e.g., NaBH(OAc).sub.3. and the reaction is
allowed to proceed proceed to completion to yield the product (6B).
The product is purified and characterized using standard methods.
1716
[0378] The compounds of the invention can also be synthesized using
Heck-type cross coupling reactions. As shown in Scheme 7, Heck-type
cross-couplings can be performed by suspending a halogenated
tetracycline compound (e.g., 7-iodo 4-dedimethylamino sancycline,
7A) and an appropriate palladium or other transition metal catalyst
(e.g., Pd(OAc).sub.2 and CuI) in an appropriate solvent (e.g.,
degassed acetonitrile). The substrate, a reactive alkene (7B) or
alkyne (7D), and triethylamine are then added and the mixture is
heated for several hours, before being cooled to room temperature.
The resulting 7-substituted alkenyl (7C) or 7-substituted alkynyl
(7E) 4-dedimethylamino tetracycline compound can then be purified
using techniques known in the art. 1717
[0379] Generally, 7,9-substituted 4-dedimethylamino tetracycline
compounds can be synthesized as shown in Scheme 9 for
4-dedimethylamino sancycline. 4-Dedimethylamino sancycline (9A) is
treated with sulfuric acid and sodium nitrate. The resulting
product is 7,9-nitro 4-dedimethylamino sancycline (9B). The nitro
4-dedimethylamino sancycline compound is then treated with hydrogen
gas and a platinum catalyst to yield the 7,9-amino
4-dedimethylamino sancycline compound, 9C. To synthesize
derivatives, the 7,9-amino 4-dedimethylamino sancycline compound is
treated with HONO, to yield the diazonium salt (9D). The salt can
subsequently be treated with numerous compounds possessing an
alkene or .pi. bond functional group such as alkenes, aryls, and
alkynyls (e.g., RBr) yielding the 7,9-substituted 4-dedimethylamino
sancycline compound (9E). 1718
[0380] The 13-substituted 4-dedimethylamino methacycline compounds
of the invention can be synthesized by methods known in the art
and/or as described herein. In Scheme 10, a general synthetic
scheme for the synthesis of 13-substituted 4-dedimethylamino
methacycline compounds is shown. In this reaction,
4-dedimethylamino methacycline is coupled with a boronic acid in
the presence of a transition metal catalyst. Furthermore, other
aryl coupling reactions known in the art may also be used. 1719
[0381] As shown in Scheme 10, the 4-dedimethylamino methacycline is
reacted with a phenylboronic acid in the presence of a palladium
catalyst such as Pd(OAc).sub.2. The resulting compound can then be
purified using techniques known in the art such as preparative HPLC
and characterized. The synthesis of the compounds of the invention
are described in more detail in Example 4.
[0382] 13-substituted 4-dedimethylamino methacycline compounds
wherein R.sup.6 is an alkyl group can be synthesized using a
tertiary alcohol and an acid catalyst as shown in Scheme 11.
1720
[0383] To prepare 7-(2'-Chloro-alkenyl) 4-dedimethylamino
tetracycline compounds, the following procedure can be used.
7-(alkynyl) 4-dedimethylamino sancycline is dissolved in saturated
methanol and hydrochloric acid and stirred. The solvent is then
removed to yield the product.
[0384] 8-Substituted 4-dedimethylamino tetracycline compounds of
the invention can be synthesized by transition metal catalyzed
coupling of tetracyclines halogenated at the 8-position. For
example, many reactions between aryl halides and various reactive
species have been developed using transition metal catalysis.
Coupling of aryl halides or triflates with main group
organometallics with oxidate addition-transmetallation-re- ductive
elimination reactions has been developed and occurs using a wide
range of catalysts, such as Pd(Pd.sub.3).sub.4, Pd(dba).sub.2,
PdCl.sub.2, Pd(OAc).sub.2, and PdCl.sub.2(CH.sub.3CN).sub.2 Ligands
such as PPh.sub.3 or AsPh.sub.3 may be added to form catalysts in
situ with palladium species such as Pd(dba).sub.2 or PdCl.sub.2.
Furthermore, copper salts, such as CuCN or CuI may also be added to
further enhance the reaction. An example of a coupling using a
halogenated tetracycline compound is shown in Scheme 12. In Scheme
12, X is bromine or chlorine. 1721
[0385] The substituted tetracycline compounds of the invention can
be synthesized using organotin reagents, halogenated or triflate
tetracycline compounds, and an appropriate catalyst (e.g.,
palladium). Examples of tin reagents include, for example, ethenyl
tributyltin, ethynyl tributyltin, phenyl tributyltin, ethenyl
trimethyl tin, ethynyl trimethyl tin, etc. These Stille type
couplings are run by adding the transition metal (e.g., palladium)
catalyst to a solution of the halogenated or triflate tetracycline
compound and the organotin reagent in polar solvents. Stille type
couplings with alkynyl and alkenyl tin reagents are shown in Scheme
13, wherein X is a halogen or a triflate group. 1722
[0386] Other methods of synthesizing the 8-substituted tetracycline
compounds of the invention include coupling halogenated
tetracycline compounds to boronic acids using Suzuki type couplings
(M. J. Sharp et al. Tetrahedron Lett. 28 (1987) 5093; W. Cheng, et
al. Tetrahedron Lett. 28 (1987) 5097; Alves, A. B. et al.
Tetrahedron Lett. 29 (1988) 2135; D. Muller, et al. Tetrahedron
Lett. 32 (1991) 2135), Grignard reagents (K. Tamao et al. Bull.
Chem. Soc. Jpn. 49 (1976) 1958), or organolithium reagents (S.-I.
Murahashi et al., J. Org. Chem 44 (1979) 2408) and a transition
metal catalyst, as shown in Scheme 14. 1723
[0387] 8-halogenated 4-dedimethyl amino tetracycline compounds can
be synthesized via azidotetracyclines. The protonolysis of the aryl
azides produces 8-halo-9-amino 4-dedimethylamino tetracycline in
good yield.
[0388] The term "alkyl" includes saturated aliphatic groups,
including straight-chain alkyl groups (e.g., methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.),
branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl,
etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl
groups, and cycloalkyl substituted alkyl groups. The term alkyl
further includes alkyl groups, which can further include oxygen,
nitrogen, sulfur or phosphorous atoms replacing one or more carbons
of the hydrocarbon backbone. In certain embodiments, a straight
chain or branched chain alkyl has 6 or fewer carbon atoms in its
backbone (e.g., C.sub.1-C.sub.6 for straight chain, C.sub.3-C.sub.6
for branched chain), and more preferably 4 or fewer. Likewise,
preferred cycloalkyls have from 3-8 carbon atoms in their ring
structure, and more preferably have 5 or 6 carbons in the ring
structure. The term C.sub.1-C.sub.6 includes alkyl groups
containing 1 to 6 carbon atoms.
[0389] Moreover, the term alkyl includes both "unsubstituted
alkyls" and "substituted alkyls", the latter of which refers to
alkyl moieties having substituents replacing a hydrogen on one or
more carbons of the hydrocarbon backbone. Such substituents can
include, for example, alkenyl, alkynyl, halogen, hydroxyl,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
Cycloalkyls can be further substituted, e.g., with the substituents
described above. An "alkylaryl" or an "arylalkyl" moiety is an
alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). The
term "alkyl" also includes the side chains of natural and unnatural
amino acids.
[0390] The term "aryl" includes groups, including 5- and 6-membered
single-ring aromatic groups that may include from zero to four
heteroatoms, for example, benzene, phenyl, pyrrole, furan,
thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole,
pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and
pyrimidine, and the like. Furthermore, the term "aryl" includes
multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g.,
naphthalene, benzoxazole, benzodioxazole, benzothiazole,
benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline,
isoquinoline, napthridine, indole, benzofuran, purine, benzofuran,
deazapurine, or indolizine. Those aryl groups having heteroatoms in
the ring structure may also be referred to as "aryl heterocycles",
"heterocycles," "heteroaryls" or "heteroaromatics". The aromatic
ring can be substituted at one or more ring positions with such
substituents as described above, as for example, halogen, hydroxyl,
alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
Aryl groups can also be fused or bridged with alicyclic or
heterocyclic rings which are not aromatic so as to form a polycycle
(e.g., tetralin).
[0391] The term "alkenyl" includes unsaturated aliphatic groups
analogous in length and possible substitution to the alkyls
described above, but that contain at least one double bond.
[0392] For example, the term "alkenyl" includes straight-chain
alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl,
hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain
alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or
alkenyl substituted cycloalkenyl groups, and cycloalkyl or
cycloalkenyl substituted alkenyl groups. The term alkenyl further
includes alkenyl groups which include oxygen, nitrogen, sulfur or
phosphorous atoms replacing one or more carbons of the hydrocarbon
backbone. In certain embodiments, a straight chain or branched
chain alkenyl group has 6 or fewer carbon atoms in its backbone
(e.g., C.sub.2-C.sub.6 for straight chain, C.sub.3-C.sub.6 for
branched chain). Likewise, cycloalkenyl groups may have from 3-8
carbon atoms in their ring structure, and more preferably have 5 or
6 carbons in the ring structure. The term C.sub.2-C.sub.6 includes
alkenyl groups containing 2 to 6 carbon atoms.
[0393] Moreover, the term alkenyl includes both "unsubstituted
alkenyls" and "substituted alkenyls", the latter of which refers to
alkenyl moieties having substituents replacing a hydrogen on one or
more carbons of the hydrocarbon backbone. Such substituents can
include, for example, alkyl groups, alkynyl groups, halogens,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety.
[0394] The term "alkynyl" includes unsaturated aliphatic groups
analogous in length and possible substitution to the alkyls
described above, but which contain at least one triple bond.
[0395] For example, the term "alkynyl" includes straight-chain
alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl,
hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain
alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl
groups. The term alkynyl further includes alkynyl groups which
include oxygen, nitrogen, sulfur or phosphorous atoms replacing one
or more carbons of the hydrocarbon backbone. In certain
embodiments, a straight chain or branched chain alkynyl group has 6
or fewer carbon atoms in its backbone (e.g., C.sub.2-C.sub.6 for
straight chain, C.sub.3-C.sub.6 for branched chain). The term
C.sub.2-C.sub.6 includes alkynyl groups containing 2 to 6 carbon
atoms.
[0396] Moreover, the term alkynyl includes both "unsubstituted
alkynyls" and "substituted alkynyls", the latter of which refers to
alkynyl moieties having substituents replacing a hydrogen on one or
more carbons of the hydrocarbon backbone. Such substituents can
include, for example, alkyl groups, alkynyl groups, halogens,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety.
[0397] Unless the number of carbons is otherwise specified, "lower
alkyl" as used herein means an alkyl group, as defined above, but
having from one to five carbon atoms in its backbone structure.
"Lower alkenyl" and "lower alkynyl" have chain lengths of, for
example, 2-5 carbon atoms.
[0398] The term "acyl" includes compounds and moieties which
contain the acyl radical (CH.sub.3CO--) or a carbonyl group. It
includes substituted acyl moieties. The term "substituted acyl"
includes acyl groups where one or more of the hydrogen atoms are
replaced by for example, alkyl groups, alkynyl groups, halogens,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety.
[0399] The term "acylamino" includes moieties wherein an acyl
moiety is bonded to an amino group. For example, the term includes
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido
groups.
[0400] The term "aroyl" includes compounds and moieties with an
aryl or heteroaromatic moiety bound to a carbonyl group. Examples
of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
[0401] The terms "alkoxyalkyl", "alkylaminoalkyl" and
"thioalkoxyalkyl" include alkyl groups, as described above, which
further include oxygen, nitrogen or sulfur atoms replacing one or
more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or
sulfur atoms.
[0402] The term "alkoxy" includes substituted and unsubstituted
alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen
atom. Examples of alkoxy groups include methoxy, ethoxy,
isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of
substituted alkoxy groups include halogenated alkoxy groups. The
alkoxy groups can be substituted with groups such as alkenyl,
alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.
Examples of halogen substituted alkoxy groups include, but are not
limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
chloromethoxy, dichloromethoxy, trichloromethoxy, etc.
[0403] The term "amine" or "amino" includes compounds where a
nitrogen atom is covalently bonded to at least one carbon or
heteroatom. The term includes "alkyl amino" which comprises groups
and compounds wherein the nitrogen is bound to at least one
additional alkyl group. The term "dialkyl amino" includes groups
wherein the nitrogen atom is bound to at least two additional alkyl
groups. The term "arylamino" and "diarylamino" include groups
wherein the nitrogen is bound to at least one or two aryl groups,
respectively. The term "alkylarylamino," "alkylaminoaryl" or
"arylaminoalkyl" refers to an amino group which is bound to at
least one alkyl group and at least one aryl group. The term
"alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bound
to a nitrogen atom which is also bound to an alkyl group.
[0404] The term "amide," "amido" or "aminocarbonyl" includes
compounds or moieties which contain a nitrogen atom which is bound
to the carbon of a carbonyl or a thiocarbonyl group. The term
includes "alkaminocarbonyl" or "alkylaminocarbonyl" groups which
include alkyl, alkenyl, aryl or alkynyl groups bound to an amino
group bound to a carbonyl group. It includes arylaminocarbonyl and
arylcarbonylamino groups which include aryl or heteroaryl moieties
bound to an amino group which is bound to the carbon of a carbonyl
or thiocarbonyl group. The terms "alkylaminocarbonyl,"
"alkenylaminocarbonyl," "alkynylaminocarbonyl,"
"arylaminocarbonyl," "alkylcarbonylamino," "alkenylcarbonylamino,"
"alkynylcarbonylamino," and "arylcarbonylamino" are included in
term "amide." Amides also include urea groups (aminocarbonylamino)
and carbamates (oxycarbonylamino).
[0405] The term "carbonyl" or "carboxy" includes compounds and
moieties which contain a carbon connected with a double bond to an
oxygen atom. The carbonyl can be further substituted with any
moiety which allows the compounds of the invention to perform its
intended function. For example, carbonyl moieties may be
substituted with alkyls, alkenyls, alkynyls, aryls, alkoxy, aminos,
etc. Examples of moieties which contain a carbonyl include
aldehydes, ketones, carboxylic acids, amides, esters, anhydrides,
etc.
[0406] The term "thiocarbonyl" or "thiocarboxy" includes compounds
and moieties which contain a carbon connected with a double bond to
a sulfur atom.
[0407] The term "ether" includes compounds or moieties which
contain an oxygen bonded to two different carbon atoms or
heteroatoms. For example, the term includes "alkoxyalkyl" which
refers to an alkyl, alkenyl, or alkynyl group covalently bonded to
an oxygen atom which is covalently bonded to another alkyl
group.
[0408] The term "ester" includes compounds and moieties which
contain a carbon or a heteroatom bound to an oxygen atom which is
bonded to the carbon of a carbonyl group. The term "ester" includes
alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl,
alkenyl, or alkynyl groups are as defined above.
[0409] The term "thioether" includes compounds and moieties which
contain a sulfur atom bonded to two different carbon or hetero
atoms. Examples of thioethers include, but are not limited to
alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term
"alkthioalkyls" include compounds with an alkyl, alkenyl, or
alkynyl group bonded to a sulfur atom which is bonded to an alkyl
group. Similarly, the term "alkthioalkenyls" and
alkthioalkynyls"refer to compounds or moieties wherein an alkyl,
alkenyl, or alkynyl group is bonded to a sulfur atom which is
covalently bonded to an alkynyl group.
[0410] The term "hydroxy" or "hydroxyl" includes groups with an
--OH or --O.sup.-.
[0411] The term "halogen" includes fluorine, bromine, chlorine,
iodine, etc. The term "perhalogenated" generally refers to a moiety
wherein all hydrogens are replaced by halogen atoms.
[0412] The terms "polycyclyl" or "polycyclic radical" refer to two
or more cyclic rings (e.g., cycloalkyls, cycloalkenyls,
cycloalkynyls, aryls and/or heterocyclyls) in which two or more
carbons are common to two adjoining rings, e.g., the rings are
"fused rings". Rings that are joined through non-adjacent atoms are
termed "bridged" rings. Each of the rings of the polycycle can be
substituted with such substituents as described above, as for
example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkoxycarbonyl, alkylaminoacarbonyl, arylalkylaminocarbonyl,
alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkyl
carbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl,
alkoxyl, phosphate, phosphonato, phosphinato, cyano, amido, amino
(including alkyl amino, dialkylamino, arylamino, diarylamino, and
alkylarylamino), acylamino (including alkylcarbonylamino,
arylcarbonylamino, carbamoyl and ureido), amidino, imino,
sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or
an aromatic or heteroaromatic moiety.
[0413] The term "heteroatom" includes atoms of any element other
than carbon or hydrogen. Preferred heteroatoms are nitrogen,
oxygen, sulfur and phosphorus.
[0414] The term "prodrug moiety" includes moieties which can be
metabolized in vivo to a hydroxyl group and moieties which may
advantageously remain esterified in vivo. Preferably, the prodrugs
moieties are metabolized in vivo by esterases or by other
mechanisms to hydroxyl groups or other advantageous groups.
Examples of prodrugs and their uses are well known in the art (See,
e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.
66:1-19). The prodrugs can be prepared in situ during the final
isolation and purification of the compounds, or by separately
reacting the purified compound in its free acid form or hydroxyl
with a suitable esterifying agent. Hydroxyl groups can be converted
into esters via treatment with a carboxylic acid. Examples of
prodrug moieties include substituted and unsubstituted, branch or
unbranched lower alkyl ester moieties, (e.g., propionoic acid
esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl
esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl
esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters
(e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester),
aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g.,
with methyl, halo, or methoxy substituents) aryl and aryl-lower
alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides,
and hydroxy amides. Preferred prodrug moieties are propionoic acid
esters and acyl esters.
[0415] It will be noted that the structure of some of the
tetracycline compounds of this invention includes asymmetric carbon
atoms. It is to be understood accordingly that the isomers arising
from such asymmetry (e.g., all enantiomers and diastereomers) are
included within the scope of this invention, unless indicated
otherwise. Such isomers can be obtained in substantially pure form
by classical separation techniques and by stereochemically
controlled synthesis. Furthermore, the structures and other
compounds and moieties discussed in this application also include
all tautomers thereof.
VI. Methods for Treating Tetracycline Responsive States
[0416] The invention also pertains to methods for treating a
tetracycline responsive states in subjects, by administering to a
subject an effective amount of a 4-dedimethylamino tetracycline
compound of the invention (e.g., of Formula I, II, III, IV, V, VI,
VII, VIII or Table 2), such that the tetracycline responsive state
is treated.
[0417] The term "treating" includes curing as well as ameliorating
at least one symptom of the state, disease or disorder, e.g., the
tetracycline compound responsive state.
[0418] The language "tetracycline compound responsive state" or
"tetracycline responsive state" includes states which can be
treated, prevented, or otherwise ameliorated by the administration
of a tetracycline compound of the invention, e.g., a
4-dedimethylamino tetracycline compound (e.g., of Formula I, II,
III, IV, V, VI, VII, VIII or Table 2). Tetracycline compound
responsive states include bacterial infections (including those
which are resistant to other tetracycline compounds), cancer (e.g.,
prostate, breast, colon, lung melanoma and lymph cancers and other
disorders characheterized by unwanted cellular proliferation,
including, but not limited to, those described in U.S. Pat. No.
6,100,248), arthritis, osteoporosis, diabetes, and other states for
which tetracycline compounds have been found to be active (see, for
example, U.S. Pat. Nos. 5,789,395; 5,834,450; 6,277,061 and
5,532,227, each of which is expressly incorporated herein by
reference). Compounds of the invention can be used to prevent or
control important mammalian and veterinary diseases such as
diarrhea, urinary tract infections, infections of skin and skin
structure, ear, nose and throat infections, wound infection,
mastitis and the like. In addition, methods for treating neoplasms
using tetracycline compounds of the invention are also included
(van der Bozert et al., Cancer Res., 48:6686-6690 (1988)). Other
examples of tetracycline associated states are described in U.S.
Ser. Nos. 10/196,010 and 60/421,248, which are incorporated herein
by reference.
[0419] In a further embodiment, the tetracycline responsive state
is not a bacterial infection. In another embodiment, the
tetracycline compounds of the invention are essentially
non-antibacterial. For example, non-antibacterial tetracycline
compounds of the invention may have MIC values greater than about 4
.mu.g/ml (as measured by assays known in the art and/or the assay
given in Example 6).
[0420] Tetracycline compound responsive states also include
inflammatory process associated states (IPAF). The term
"inflammatory process associated state" includes states in which
inflammation or inflammatory factors (e.g., matrix
metalloproteinases (MMPs), nitric oxide (NO), TNF, interleukins,
plasma proteins, cellular defense systems, cytokines, lipid
metabolites, proteases, toxic radicals, adhesion molecules, etc.)
are involved or are present in an area in aberrant amounts, e.g.,
in amounts which may be advantageous to alter, e.g., to benefit the
subject. The inflammatory process is the response of living tissue
to damage. The cause of inflammation may be due to physical damage,
chemical substances, micro-organisms, tissue necrosis, cancer or
other agents. Acute inflammation is short-lasting, lasting only a
few days. If it is longer lasting however, then it may be referred
to as chronic inflammation.
[0421] IPAF's include inflammatory disorders. Inflammatory
disorders are generally characterized by heat, redness, swelling,
pain and loss of function. Examples of causes of inflammatory
disorders include, but are not limited to, microbial infections
(e.g., bacterial and fungal infections), physical agents (e.g.,
burns, radiation, and trauma), chemical agents (e.g., toxins and
caustic substances), tissue necrosis and various types of
immunologic reactions.
[0422] Examples of inflammatory disorders include, but are not
limited to, osteoarthritis, rheumatoid arthritis, acute and chronic
infections (bacterial and fungal, including diphtheria and
pertussis); acute and chronic bronchitis, sinusitis, and upper
respiratory infections, including the common cold; acute and
chronic gastroenteritis and colitis; acute and chronic cystitis and
urethritis; acute and chronic dermatitis; acute and chronic
conjunctivitis; acute and chronic serositis (pericarditis,
peritonitis, synovitis, pleuritis and tendinitis); uremic
pericarditis; acute and chronic cholecystis; acute and chronic
vaginitis; acute and chronic uveitis; drug reactions; insect bites;
burns (thermal, chemical, and electrical); and sunburn.
[0423] Tetracycline compound responsive states also include NO
associated states. The term "NO associated state" includes states
which involve or are associated with nitric oxide (NO) or inducible
nitric oxide synthase (iNOS). NO associated state includes states
which are characterized by aberrant amounts of NO and/or iNOS.
Preferably, the NO associated state can be treated by administering
tetracycline compounds of the invention (e.g., of Formula I, II,
III, IV, V, VI, VII, VIII or Table 2). In certain embodiments, the
invention includes 7-substituted 4-dedimethylamino tetracyclines.
The disorders, diseases and states described in U.S. Pat. Nos.
6,231,894; 6,015,804; 5,919,774; and 5,789,395 are also included as
NO associated states. The entire contents of each of these patents
are hereby incorporated herein by reference.
[0424] Other examples of NO associated states include, but are not
limited to, malaria, senescence, diabetes, vascular stroke,
neurodegenerative disorders (Alzheimer's disease & Huntington's
disease), cardiac disease (re-perfusion-associated injury following
infarction), juvenile diabetes, inflammatory disorders,
osteoarthritis, rheumatoid arthritis, acute and chronic infections
(bacterial and fungal, including diphtheria and pertussis); acute
and chronic bronchitis, sinusitis, and upper respiratory
infections, including the common cold; acute and chronic
gastroenteritis and colitis; acute and chronic cystitis and
urethritis; acute and chronic dermatitis; acute and chronic
conjunctivitis; acute and chronic serositis (pericarditis,
peritonitis, synovitis, pleuritis and tendinitis); uremic
pericarditis; acute and chronic cholecystis; acute and chronic
vaginitis; acute and chronic uveitis; drug reactions; insect bites;
burns (thermal, chemical, and electrical); and sunburn.
[0425] The term "inflammatory process associated state" also
includes, in one embodiment, matrix metalloproteinase associated
states (MMPAS). MMPAS include states charachterized by abberrant
amounts of MMPs or MMP activity. These are also include as
tetracycline compound responsive states which may be treated using
compounds of the invention, e.g., 4-dedimethylamino tetracycline
compounds such as those described herein (e.g., of Formula I, II,
III, IV, V, VI, VII, VIII or Table 2).
[0426] Examples of matrix metalloproteinase associated states
("MMPAS's") include, but are not limited to, arteriosclerosis,
corneal ulceration, emphysema, osteoarthritis, multiple
sclerosis(Liedtke et al., Ann. Neurol. 1998, 44:35-46; Chandler et
al., J Neuroimmunol. 1997, 72:155-71), osteosarcoma, osteomyelitis,
bronchiectasis, chronic pulmonary obstructive disease, skin and eye
diseases, periodontitis, osteoporosis, rheumatoid arthritis,
ulcerative colitis, inflammatory disorders, tumor growth and
invasion (Stetler-Stevenson et al., Annu. Rev. Cell Biol. 1993,
9:541-73; Tryggvason et al., Biochim. Biophys. Acta 1987,
907:191-217; Li et al., Mol. Carcinog. 1998, 22:84-89)),metastasis,
acute lung injury, stroke, ischemia, diabetes, aortic or vascular
aneurysms, skin tissue wounds, dry eye, bone and cartilage
degradation (Greenwald et al., Bone 1998, 22:33-38; Ryan et al.,
Curr. Op. Rheumatol. 1996, 8;238-247). Other MMPAS include those
described in U.S. Pat. Nos. 5,459,135; 5,321,017; 5,308,839;
5,258,371; 4,935,412; 4,704,383, 4,666,897, and RE 34,656,
incorporated herein by reference in their entirety.
[0427] In another embodiment, the tetracycline compound responsive
state is cancer. Examples of cancers which the tetracycline
compounds of the invention may be useful to treat include all solid
tumors, i.e., carcinomas e.g., adenocarcinomas, and sarcomas.
Adenocarcinomas are carcinomas derived from glandular tissue or in
which the tumor cells form recognizable glandular structures.
Sarcomas broadly include tumors whose cells are embedded in a
fibrillar or homogeneous substance like embryonic connective
tissue. Examples of carcinomas which may be treated using the
methods of the invention include, but are not limited to,
carcinomas of the prostate, breast, ovary, testis, lung, colon, and
breast. The methods of the invention are not limited to the
treatment of these tumor types, but extend to any solid tumor
derived from any organ system. Examples of treatable cancers
include, but are not limited to, colon cancer, bladder cancer,
breast cancer, melanoma, ovarian carcinoma, prostatic carcinoma,
lung cancer, and a variety of other cancers as well. The methods of
the invention also cause the inhibition of cancer growth in
adenocarcinomas, such as, for example, those of the prostate,
breast, kidney, ovary, testes, and colon.
[0428] In an embodiment, the tetracycline responsive state of the
invention is cancer. The invention pertains to a method for
treating a subject suffering or at risk of suffering from cancer,
by administering an effective amount of a substituted tetracycline
compound, such that inhibition cancer cell growth occurs, i.e.,
cellular proliferation, invasiveness, metastasis, or tumor
incidence is decreased, slowed, or stopped. The inhibition may
result from inhibition of an inflammatory process, down-regulation
of an inflammatory process, some other mechanism, or a combination
of mechanisms. Alternatively, the tetracycline compounds may be
useful for preventing cancer recurrence, for example, to treat
residual cancer following surgical resection or radiation therapy.
The tetracycline compounds useful according to the invention are
especially advantageous as they are substantially non-toxic
compared to other cancer treatments. In a further embodiment, the
compounds of the invention are administered in combination with
standard cancer therapy, such as, but not limited to,
chemotherapy.
[0429] The language "in combination with" another therapeutic agent
or treatment includes co-administration of the tetracycline
compound, (e.g., inhibitor) and with the other therapeutic agent or
treatment, administration of the tetracycline compound first,
followed by the other therapeutic agent or treatment and
administration of the other therapeutic agent or treatment first,
followed by the tetracycline compound. The other therapeutic agent
may be any agent which is known in the art to treat, prevent, or
reduce the symptoms of an IPAS. Furthermore, the other therapeutic
agent may be any agent of benefit to the patient when administered
in combination with the administration of an tetracycline compound.
In one embodiment, the cancers treated by methods of the invention
include those described in U.S. Pat. Nos. 6,100,248; 5,843,925;
5,837,696; or 5,668,122, incorporated herein by reference in their
entirety.
[0430] In another embodiment, the tetracycline compound responsive
state is diabetes, e.g., juvenile diabetes, diabetes mellitus,
diabetes type I, or diabetes type II. In a further embodiment,
protein glycosylation is not affected by the administration of the
tetracycline compounds of the invention. In another embodiment, the
tetracycline compound of the invention is administered in
combination with standard diabetic therapies, such as, but not
limited to insulin therapy. In a further embodiment, the IPAS
includes disorders described in U.S. Pat. Nos. 5,929,055; and
5,532,227, incorporated herein by reference in their entirety.
[0431] In another embodiment, the tetracycline compound responsive
state is a bone mass disorder. Bone mass disorders include
disorders where a subjects bones are disorders and states where the
formation, repair or remodeling of bone is advantageous. For
examples bone mass disorders include osteoporosis (e.g., a decrease
in bone strength and density), bone fractures, bone formation
associated with surgical procedures (e.g., facial reconstruction),
osteogenesis imperfecta (brittle bone disease), hypophosphatasia,
Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone
disease, and the depletion of calcium in bone, such as that which
is related to primary hyperparathyroidism. Bone mass disorders
include all states in which the formation, repair or remodeling of
bone is advantageous to the subject as well as all other disorders
associated with the bones or skeletal system of a subject which can
be treated with the tetracycline compounds of the invention. In a
further embodiment, the bone mass disorders include those described
in U.S. Pat. Nos. 5,459,135; 5,231,017; 5,998,390; 5,770,588; RE
34,656; 5,308,839; 4,925,833; 3,304,227; and 4,666,897, each of
which is hereby incorporated herein by reference in its
entirety.
[0432] In another embodiment, the tetracycline compound responsive
state is acute lung injury. Acute lung injuries include adult
respiratory distress syndrome (ARDS), post-pump syndrome (PPS), and
trauma. Trauma includes any injury to living tissue caused by an
extrinsic agent or event. Examples of trauma include, but are not
limited to, crush injuries, contact with a hard surface, or cutting
or other damage to the lungs.
[0433] The invention also pertains to a method for treating acute
lung injury by administering a substituted tetracycline compound of
the invention.
[0434] The tetracycline responsive states of the invention also
include chronic lung disorders. The invention pertains to methods
for treating chronic lung disorders by administering a tetracycline
compound, such as those described herein. The method includes
administering to a subject an effective amount of a substituted
tetracycline compound such that the chronic lung disorder is
treated. Examples of chronic lung disorders include, but are not
limited, to asthma, cystic fibrosis, and emphesema. In a further
embodiment, the tetracycline compounds of the invention used to
treat acute and/or chronic lung disorders such as those described
in U.S. Pat. Nos. 5,977,091; 6,043,231; 5,523,297; and 5,773,430,
each of which is hereby incorporated herein by reference in its
entirety.
[0435] In yet another embodiment, the tetracycline compound
responsive state is ischemia, stroke, or ischemic stroke. The
invention also pertains to a method for treating ischemia, stroke,
or ischemic stroke by administering an effective amount of a
substituted tetracycline compound of the invention. In a further
embodiment, the tetracycline compounds of the invention are used to
treat such disorders as described-in U.S. Pat. Nos. 6,231,894;
5,773,430; 5,919,775 or 5,789,395, incorporated herein by
reference.
[0436] In another embodiment, the tetracycline compound responsive
state is a skin wound. The invention also pertains, at least in
part, to a method for improving the healing response of the
epithelialized tissue (e.g., skin, mucusae) to acute traumatic
injury (e.g., cut, burn, scrape, etc.). The method may include
using a tetracycline compound of the invention (which may or may
not have antibacterial activity) to improve the capacity of the
epithelialized tissue to heal acute wounds. The method may increase
the rate of collagen accumulation of the healing tissue. The method
may also decrease the proteolytic activity in the epthithelialized
tissue by decreasing the collagenolytic and/or gellatinolytic
activity of MMPs. In a further embodiment, the tetracycline
compound of the invention is administered to the surface of the
skin (e.g., topically). In a further embodiment, the tetracycline
compound of the invention used to treat a skin wound, and other
such disorders as described in, for example, U.S. Pat. Nos.
5,827,840; 4,704,383; 4,935,412; 5,258,371; 5,308,8391 5,459,135;
5,532,227; and 6,015,804; each of which is incorporated herein by
reference in its entirety.
[0437] In yet another embodiment, the tetracycline compound
responsive state is an aortic or vascular aneurysm in vascular
tissue of a subject (e.g., a subject having or at risk of having an
aortic or vascular aneurysm, etc.). The tetracycline compound may
by effective to reduce the size of the vascular aneurysm or it may
be administered to the subject prior to the onset of the vascular
aneurysm such that the aneurysm is prevented. In one embodiment,
the vascular tissue is an artery, e.g., the aorta, e.g., the
abdominal aorta. In a further embodiment, the tetracycline
compounds of the invention are used to treat disorders described in
U.S. Pat. Nos. 6,043,225 and 5,834,449, incorporated herein by
reference in their entirety.
[0438] Bacterial infections may be caused by a wide variety of gram
positive and gram negative bacteria. The compounds of the invention
are useful as antibiotics against organisms which are resistant to
other tetracycline compounds. The antibiotic activity of the
tetracycline compounds of the invention may be determined using the
method discussed in Example 2, or by using the in vitro standard
broth dilution method described in Waitz, J. A., National
Commission for Clinical Laboratory Standards, Document M7-A2, vol.
10, no. 8, pp.13-20, 2.sup.nd edition, Villanova, Pa. (1990).
[0439] The tetracycline compounds may also be used to treat
infections traditionally treated with tetracycline compounds such
as, for example, rickettsiae; a number of gram-positive and
gram-negative bacteria; and the agents responsible for
lymphogranuloma venereum, inclusion conjunctivitis, psittacosis.
The tetracycline compounds may be used to treat infections of,
e.g., K. pneumoniae, Salmonella, E. hirae, A. baumanii, B.
catarrhalis, H. influenzae, P. aeruginosa, E. faecium, E. coli, S.
aureus or E. faecalis. In one embodiment, the tetracycline compound
is used to treat a bacterial infection that is resistant to other
tetracycline antibiotic compounds. The tetracycline compound of the
invention may be administered with a pharmaceutically acceptable
carrier.
[0440] The language "effective amount" of the compound is that
amount necessary or sufficient to treat or prevent a tetracycline
compound responsive state. The effective amount can vary depending
on such factors as the size and weight of the subject, the type of
illness, or the particular tetracycline compound. For example, the
choice of the tetracycline compound can affect what constitutes an
"effective amount". One of ordinary skill in the art would be able
to study the aforementioned factors and make the determination
regarding the effective amount of the tetracycline compound without
undue experimentation.
[0441] The invention also pertains to methods of treatment against
microorganism infections and associated diseases. The methods
include administration of an effective amount of one or more
tetracycline compounds to a subject. The subject can be either a
plant or, advantageously, an animal, e.g., a mammal, e.g., a
human.
[0442] In the therapeutic methods of the invention, one or more
tetracycline compounds of the invention may be administered alone
to a subject, or more typically a compound of the invention will be
administered as part of a pharmaceutical composition in mixture
with conventional excipient, i.e., pharmaceutically acceptable
organic or inorganic carrier substances suitable for parenteral,
oral or other desired administration and which do not deleteriously
react with the active compounds and are not deleterious to the
recipient thereof.
VII. Pharmaceutical Compositions
[0443] The invention also pertains to pharmaceutical compositions
comprising a therapeutically effective amount of a
4-dedimethylamino tetracycline compound (e.g., a compound of
Formula I, II, III, IV, V, VI, VII, VIII or Table 2) and,
optionally, a pharmaceutically acceptable carrier.
[0444] The language "pharmaceutically acceptable carrier" includes
substances capable of being coadministered with the tetracycline
compound(s), and which allow both to perform their intended
function, e.g., treat or prevent a tetracycline responsive state.
Suitable pharmaceutically acceptable carriers include but are not
limited to water, salt solutions, alcohol, vegetable oils,
polyethylene glycols, gelatin, lactose, amylose, magnesium
stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty
acid monoglycerides and diglycerides, petroethral fatty acid
esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The
pharmaceutical preparations can be sterilized and if desired mixed
with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure, buffers, colorings, flavorings and/or aromatic
substances and the like which do not deleteriously react with the
active compounds of the invention.
[0445] The tetracycline compounds of the invention that are basic
in nature are capable of forming a wide variety of salts with
various inorganic and organic acids. The acids that may be used to
prepare pharmaceutically acceptable acid addition salts of the
tetracycline compounds of the invention that are basic in nature
are those that form non-toxic acid addition salts, i.e., salts
containing pharmaceutically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,
bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and palmoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3-na- phthoate)] salts. Although such
salts must be pharmaceutically acceptable for administration to a
subject, e.g., a mammal, it is often desirable in practice to
initially isolate a tetracycline compound of the invention from the
reaction mixture as a pharmaceutically unacceptable salt and then
simply convert the latter back to the free base compound by
treatment with an alkaline reagent and subsequently convert the
latter free base to a pharmaceutically acceptable acid addition
salt. The acid addition salts of the base compounds of this
invention are readily prepared by treating the base compound with a
substantially equivalent amount of the chosen mineral or organic
acid in an aqueous solvent medium or in a suitable organic solvent,
such as methanol or ethanol. Upon careful evaporation of the
solvent, the desired solid salt is readily obtained. The
preparation of other tetracycline compounds of the invention not
specifically described in the foregoing experimental section can be
accomplished using combinations of the reactions described above
that will be apparent to those skilled in the art.
[0446] The preparation of other tetracycline compounds of the
invention not specifically described in the foregoing experimental
section can be accomplished using combinations of the reactions
described above that will be apparent to those skilled in the
art.
[0447] The tetracycline compounds of the invention that are acidic
in nature are capable of forming a wide variety of base salts. The
chemical bases that may be used as reagents to prepare
pharmaceutically acceptable base salts of those tetracycline
compounds of the invention that are acidic in nature are those that
form non-toxic base salts with such compounds. Such non-toxic base
salts include, but are not limited to those derived from such
pharmaceutically acceptable cations such as alkali metal cations
(e.g., potassium and sodium) and alkaline earth metal cations
(e.g., calcium and magnesium), ammonium or water-soluble amine
addition salts such as N-methylglucamine-(meglumine), and the lower
alkanolammonium and other base salts of pharmaceutically acceptable
organic amines. The pharmaceutically acceptable base addition salts
of tetracycline compounds of the invention that are acidic in
nature may be formed with pharmaceutically acceptable cations by
conventional methods. Thus, these salts may be readily prepared by
treating the tetracycline compound of the invention with an aqueous
solution of the desired pharmaceutically acceptable cation and
evaporating the resulting solution to dryness, preferably under
reduced pressure. Alternatively, a lower alkyl alcohol solution of
the tetracycline compound of the invention may be mixed with an
alkoxide of the desired metal and the solution subsequently
evaporated to dryness.
[0448] The preparation of other tetracycline compounds of the
invention not specifically described in the foregoing experimental
section can be accomplished using combinations of the reactions
described above that will be apparent to those skilled in the
art.
[0449] The tetracycline compounds of the invention and
pharmaceutically acceptable salts thereof can be administered via
either the oral, parenteral or topical routes. In general, these
compounds are most desirably administered in effective dosages,
depending upon the weight and condition of the subject being
treated and the particular route of administration chosen.
Variations may occur depending upon the species of the subject
being treated and its individual response to said medicament, as
well as on the type of pharmaceutical formulation chosen and the
time period and interval at which such administration is carried
out.
[0450] The pharmaceutical compositions of the invention may be
administered alone or in combination with other known compositions
for treating tetracycline responsive states in a subject, e.g., a
mammal. Preferred mammals include pets (e.g., cats, dogs, ferrets,
etc.), farm animals (cows, sheep, pigs, horses, goats, etc.), lab
animals (rats, mice, monkeys, etc.), and primates (chimpanzees,
humans, gorillas). The language "in combination with" a known
composition is intended to include simultaneous administration of
the composition of the invention and the known composition,
administration of the composition of the invention first, followed
by the known composition and administration of the known
composition first, followed by the composition of the invention.
Any of the therapeutically composition known in the art for
treating tetracycline responsive states can be used in the methods
of the invention.
[0451] The tetracycline compounds of the invention may be
administered alone or in combination with pharmaceutically
acceptable carriers or diluents by any of the routes previously
mentioned, and the administration may be carried out in single or
multiple doses. For example, the novel therapeutic agents of this
invention can be administered advantageously in a wide variety of
different dosage forms, i.e., they may be combined with various
pharmaceutically acceptable inert carriers in the form of tablets,
capsules, lozenges, troches, hard candies, powders, sprays, creams,
salves, suppositories, jellies, gels, pastes, lotions, ointments,
aqueous suspensions, injectable solutions, elixirs, syrups, Land
the like. Such carriers include solid diluents or fillers, sterile
aqueous media and various non-toxic organic solvents, etc.
Moreover, oral pharmaceutical compositions can be suitably
sweetened and/or flavored. In general, the
therapeutically-effective compounds of this invention are present
in such dosage forms at concentration levels ranging from about
5.0% to about 70% by weight.
[0452] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dicalcium phosphate and glycine may be employed
along with various disintegrants such as starch (and preferably
corn, potato or tapioca starch), alginic acid and certain complex
silicates, together with granulation binders like
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often very useful for tabletting purposes.
Solid compositions of a similar type may also be employed as
fillers in gelatin capsules; preferred materials in this connection
also include lactose or milk sugar as well as high molecular weight
polyethylene glycols. When aqueous suspensions and/or elixirs are
desired for oral administration, the active ingredient may be
combined with various sweetening or flavoring agents, coloring
matter or dyes, and, if so desired, emulsifying and/or suspending
agents as well, together with such diluents as water, ethanol,
propylene glycol, glycerin and various like combinations
thereof.
[0453] For parenteral administration (including intraperitoneal,
subcutaneous, intravenous, intradermal or intramuscular injection),
solutions of a therapeutic compound of the present invention in
either sesame or peanut oil or in aqueous propylene glycol may be
employed. The aqueous solutions should be suitably buffered
(preferably pH greater than 8) if necessary and the liquid diluent
first rendered isotonic. These aqueous solutions are suitable for
intravenous injection purposes. The oily solutions are suitable for
intraarticular, intramuscular and subcutaneous injection purposes.
The preparation of all these solutions under sterile conditions is
readily accomplished by standard pharmaceutical techniques well
known to those skilled in the art. For parenteral application,
examples of suitable preparations include solutions, preferably
oily or aqueous solutions as well as suspensions, emulsions, or
implants, including suppositories. Therapeutic compounds may be
formulated in sterile form in multiple or single dose formats such
as being dispersed in a fluid carrier such as sterile physiological
saline or 5% saline dextrose solutions commonly used with
injectables.
[0454] Additionally, it is also possible to administer the
compounds of the present invention topically when treating
inflammatory conditions of the skin. Examples of methods of topical
administration include transdermal, buccal or sublingual
application. For topical applications, therapeutic compounds can be
suitably admixed in a pharmacologically inert topical carrier such
as a gel, an ointment, a lotion or a cream. Such topical carriers
include water, glycerol, alcohol, propylene glycol, fatty alcohols,
triglycerides, fatty acid esters, or mineral oils. Other possible
topical carriers are liquid petrolatum, isopropylpalmitate,
polyethylene glycol, ethanol 95%, polyoxyethylene monolauriate 5%
in water, sodium lauryl sulfate 5% in water, and the like. In
addition, materials such as anti-oxidants, humectants, viscosity
stabilizers and the like also may be added if desired.
[0455] For enteral application, particularly suitable are tablets,
dragees or capsules having talc and/or carbohydrate carrier binder
or the like, the carrier preferably being lactose and/or corn
starch and/or potato starch. A syrup, elixir or the like can be
used wherein a sweetened vehicle is employed. Sustained release
compositions can be formulated including those wherein the active
component is protected with differentially degradable coatings,
e.g., by microencapsulation, multiple coatings, etc.
[0456] In addition to treatment of human subjects, the therapeutic
methods of the invention also will have significant veterinary
applications, e.g. for treatment of livestock such as cattle,
sheep, goats, cows, swine and the like; poultry such as chickens,
ducks, geese, turkeys and the like; horses; and pets such as dogs
and cats. Also, the compounds of the invention may be used to treat
non-animal subjects, such as plants.
[0457] It will be appreciated that the actual preferred amounts of
active compounds used in a given therapy will vary according to the
specific compound being utilized, the particular compositions
formulated, the mode of application, the particular site of
administration, etc. Optimal administration rates for a given
protocol of administration can be readily ascertained by those
skilled in the art using conventional dosage determination tests
conducted with regard to the foregoing guidelines.
[0458] In general, compounds of the invention for treatment can be
administered to a subject in dosages used in prior tetracycline
therapies. See, for example, the Physicians' Desk Reference. For
example, a suitable effective dose of one or more compounds of the
invention will be in the range of from 0.01 to 100 milligrams per
kilogram of body weight of recipient per day, preferably in the
range of from 0.1 to 50 milligrams per kilogram body weight of
recipient per day, more preferably in the range of 1 to 20
milligrams per kilogram body weight of recipient per day. The
desired dose is suitably administered once daily, or several
sub-doses, e.g. 2 to 5 sub-doses, are administered at appropriate
intervals through the day, or other appropriate schedule. It will
also be understood that normal, conventionally known precautions
will be taken regarding the administration of tetracyclines
generally to ensure their efficacy under normal use circumstances.
Especially when employed for therapeutic treatment of humans and
animals in vivo, the practitioner should take all sensible
precautions to avoid conventionally known contradictions and toxic
effects. Thus, the conventionally recognized adverse reactions of
gastrointestinal distress and inflammations, the renal toxicity,
hypersensitivity reactions, changes in blood, and impairment of
absorption through aluminum, calcium, and magnesium ions should be
duly considered in the conventional manner.
[0459] Furthermore, the invention also pertains to the use of a
tetracycline compound of Formula I, II, III, IV, V, VI, VII, VIII
or Table 2 for the preparation of a medicament. The medicament may
include a pharmaceutically acceptable carrier and the tetracycline
compound is an effective amount, e.g., an effective amount to treat
a tetracycline responsive state.
EXEMPLIFICATION OF THE INVENTION
[0460] Compounds of the invention may be made as described below,
with modifications to the procedure below within the skill of those
of ordinary skill in the art.
EXAMPLE 1
Synthesis of 7-Substituted 4-Dedimethylamino Sancyclines
7 Iodo 4-Dedimethylamino Sancycline
[0461] One gram of 4-dedimethylamino sancycline is dissolved in 25
mL of TFA (trifluoroacetic acid) that was cooled to 0 C (on ice).
1.2 equivalents of N-iodosuccinimide (NIS) is added to the reaction
mixture and reacted for forty minutes. The reaction is removed from
the ice bath and allowed to react at room temperature for an
additional five hours. The mixture is then analyzed by HPLC and
TLC, and driven to completion by the stepwise addition of NIS.
After completion of the reaction, the TFA is removed in vacuo and 3
mL of MeOH is added to dissolve the residue. The methanolic
solution is added slowly to a rapidly stirring solution of the
product in diethyl ether to form a greenish brown precipitate. The
7-iodo isomer of 4-dedimethylamino sancycline is purified by
treating the 7-iodo 4-dedimethylamino product with activated
charcoal., filtering through Celite, and subsequent removal of the
solvent in vacuo to produce the 7-isomer compound as a pure
solid.
(7-Phenyl) 4-Dedimethylamino Sancycline)
[0462] 7-iodo 4-dedimethylamino sancycline, 150 mg (0.28 mM),
Pd(OAc).sub.2 and 1 0 mL of MeOH are added to a flask with a stir
bar and the system degassed three times using argon.
Na.sub.2CO.sub.3 (87 mg, 0.8 mM) dissolved in water and argon
degassed is added via syringe and is added along with phenylboronic
acid (68 mg, 0.55 mM) in MeOH that was also degassed. The reaction
is followed by HPLC for 2 hours and then the reaction mixture is
cooled to room temperature. The solution is filtered, and dried to
produce a crude mixture. The solid is dissolved in
dimethylformamide and injected onto a preparative HPLC system using
C18 reverse-phase silica. The product fraction is isolated, and the
solvent is removed in vacuo to yield the product.
7-(4'-Chlorophenyl) 4-Dedimethylamino Sancycline
[0463] 7-iodo 4-dedimethylamino sancycline, 500 mg (0.91 mM),
Pd(OAc).sub.2 21 mg, and 20 mL of MeOH are added to a flask with a
stir bar and the system is degassed 3.times. using argon.
Na.sub.2CO.sub.3 (293 mg, 2.8 mM) dissolved in water and argon
degassed is added via syringe and is added along with
4-Cl-phenylboronic acid (289 mg, 1.85 mM) in MeOH that was also
degassed. The reaction is followed by HPLC for 45 minutes and the
reaction mixture is cooled to room temperature. The solution is
filtered, and dried to produce a crude mixture. The solid is
dissolved in dimethylformamide and injected onto a preparative HPLC
system using C18 reverse-phase silica. The fraction at 39 minutes
is isolated, and the solvent is removed in vacuo to yield the
product.
7-(4'-Fluorophenyl) 4-Dedimethylamino Sancycline
[0464] 7-Iodo 4-dedimethylamino sancycline, 200 mg (0.3 mM),
Pd(OAc).sub.2 8.3 mg, and 10 mL of MeOH are added to a flask with a
stir bar and the system is degassed 3.times. using argon.
Na.sub.2CO.sub.3 (104 mg, 1.1 mM) (dissolved in water) and argon
(degassed) are added via syringe along with 4-F-phenylboronic acid
(104 mg, 0.7 mM) in MeOH which was also previously degassed. The
reaction is followed by HPLC for 20 minutes and the mixture is
cooled to room temperature. The solution is filtered, and dried to
produce a crude mixture. The solid is dissolved in
dimethylformamide and injected onto a preparative HPLC system using
C18 reverse-phase silica. The fraction containing the product is
isolated.
7-(4'-Iodo-1',3'-carboethoxy-1',3'-butadiene) 4-Dedimethylamino
Sancycline
[0465] 7-I-4-dedimethylamino sancycline (1.86 mmol) is dissolved in
25 mL of acetonitrile that was previously degassed and purged with
nitrogen (three times). To this suspension Pd(OAc).sub.2 (20 mg,
0.089 mmol), CuI (10 mg, 0.053 mmol), (o-tolyl).sub.3P (56 mg,
0.183 mmol) are added and purged with nitrogen. Ethyl propiolate (1
mL) and triethylamine (1 mL) are added to the suspension. The
reaction mixture is then heated to 70 degrees C for two hours.
Progress of the reaction is monitored by HPLC. It is then cooled
down to room temperature and filtered through celite. Evaporation
of the solvent gives the product, which is purified on preparative
HPLC.
7-(2'-Chloroethenyl)-4-Dedimethylamino Sancycline
[0466] To a solution/suspension of (1 mmol) of 7-iodo 4-dedimethyl
amino sancycline, 0.05 g tetrakis triphenyl phosphinato palladate,
0.012 g palladium acetate, 0.05 g copper (I) iodide in 10 mL
acetonitrile, 2 mL triethylamine and 0.5 g trimethylsilyl acetylene
are added at room temperature. The reaction is allowed to proceed
for two hours before being filtered through a celite bed and
concentrated. The crude product is purified by preparative HPLC.
The collected fractions are concentrated and the residue is taken
up in about 1 mL of methanol and 2 mL of HCl saturated methanol.
The product is precipitated with ether. The solids are filtered off
and dried under reduced pressure.
7-(4'-aminophenyl) 4-Dedimethylamino Sancycline
[0467] To a solution of 200 mg of 7-(4-nitrophenyl)
4-dedimethylamino sancycline in 50 mL methanol, 10 mg of 10%
palladium on charcoal catalyst is added. The reaction mixture is
shaken under 40 psi hydrogen pressure for 2 hours and is then
filtered followed by concentration. The residue is further purified
by preparative HPLC.
1,8-Di-7-4-Dedimethylamino Sancyclinyl-1,8-Heptyne
[0468] 1724
[0469] A flask was charged with 7-iodo 4-dedimethylamino sancycline
(3.0 g, 4.57 mmol, 15A), Pd(OAc).sub.2 (0.102 g, 0.46 mmol), CuI
(0.044 g, 0.23 mmol), and P(o-Tol).sub.3 (0.278 g, 0.91 mmol) and
the contents are suspended in anhydrous acetonitrile. After purging
this mixture with dinitrogen at 60.degree. C. (bath temperature),
1,7-octadiyne (0.305 mL, 2.29 mmol, 15B) is added to it, followed
by the addition of triethylamine. The solution is stirred at
60.degree. C. for 3 h, filtered through a bed of celite, and dried.
A methanol:DMF:TFA (90:8:2) solution of the product (15C) is
purified on preparative HPLC column.
7-(NN-Dimethylpropynyl)-4-Dedimethylamino Sancycline
[0470] 1725
[0471] 7-1-4-dedimethylamino sancycline (1 gm, 1.86 mmol ), taken
in 25 mL of acetonitrile, is degassed and purged with nitrogen
(three times). To this suspension Pd(OAc).sub.2 (20 mg, 0.089
mmol), CuI (10 mg, 0.053 mmol), (o-tolyl).sub.3P (56 mg, 0.183
mmol) are added and purged with nitrogen for few minutes.
NN-Dimethylpropyne (308 mg, 3.72 mmol) and triethylamine (1 mL) are
added to the suspension. The reaction mixture is then heated to
70.degree. C. for 3 hours. Progress of the reaction is monitored by
HPLC. It is then cooled down to room temperature and filtered
through celite. Evaporation of the solvent gives the product, which
is then purified on preparative HPLC.
7-(2'-Chloro-3-Hydroxypropenyl)-4-Dedimethylamino Sancycline
[0472] 1726
[0473] 7-(alkynyl)-4-dedimethylamino sancycline (100 mg) is taken
in 20 ml of saturated MeOH/HCl and stirred for 20 min. The solvent
is then evaporated to give the product.
7-(3'-Methoxyphenylethyl)-4-Dedimethylamino Sancycline
[0474] 1727
[0475] 7-(3'-Methoxyphenylethynyl)-4-dedimethylamino sancycline (1
mmol)/is taken in saturated solution of MeOH/HCl. To this solution
10% Pd/C is added and is subjected to hydrogenation at 50 psi for
12 hrs. It is then filtered through celite. The solvent is
evaporated, and the product is precipitated from
MeOH/diethylether.
(2-Dimethylamino-Acetylamino)-4-Dedimethylamino Sancycline
[0476] 1728
[0477] NN-Dimethylglycine (1.2 mmol) is dissolved in DMF (5 mL) and
O-Benzotriazol-1-yl-N, N, N', N',-tetramethyluronium
hexafluorophosphate (HBTU, 1.2 mmol) was added. The solution is
then stirred for 5 minutes at room temperature. To this solution,
7-amino 4-dedimethylamino sancycline (1 mmol, 16A) was added,
followed by the addition of diisopropylethyl amine (DIEA, 1.2
mmol). The reaction is then stirred at room temperature for 2
hours. The solvent, DMF, is removed on vaccum. The crude material
is dissolved in 5 mL of MeOH and filtered using autovials and
purified using preparative HPLC.
7-(N-Methylsulphonamidopropargylamine) 4-Dedimethylamino
Sancycline
[0478] 1729
[0479] To a mixture of 7-iodo 4-dedimethylamino sancycline mono
trifluoroacetic acid salt (1 g; 1.53 mmoles, 17A), palladium II
acetate(17.2 mg; 0.076 mmoles), tetrakis triphenylphosphine
palladium (176.8 mg; 0.153 mmoles), and copper (I) iodide(49 mg;
0.228 mmoles) is added 15 ml of reagent grade acetonitrile in a
clean dry 2 necked round bottom flask. The reaction is purged with
a slow steam of argon gas, with stirring, for 5 minutes before the
addition (in one portion as a solid) of
N-methylsulphonamidopropargyl amine (17B). The sulphonamide is
prepared by a method known in the art (J.Med.Chem 31(3) 1988;
577-82). This is followed by one milliliter of triethylamine (1 ml;
0.726 mg; 7.175 mmoles) and the reaction is stirred, under an argon
atmosphere, for approximately 1.0 hour at ambient temperature. The
reaction mixture is suctioned filtered through a pad of
diatomaceous earth and washed with acetonitrile. The filtrates are
reduced to dryness under vacuo and the residue is treated with a
dilute solution of trifluroroacetic acid in acetonitrile to adjust
the pH to approximately 2. The residue is treated with more dilute
trifluoroacetic acid in acetonitrile, resulting in the formation of
a precipitate, which is removed via suction filtration. The crude
filtrates are purified utilizing reverse phase HPLC with DVB as the
solid phase; and a gradient of 1:1 methanol/acetonitrile 1%
trifluoroacetic acid and 1% trifluoroacetic acid in water. The
appropriate fractions are reduced,to dryness under reduced pressure
and solid collected. The product is characterized via .sup.1H NMR,
mass spectrogram and LC reverse phase.
7-(2'-methoxy-5'-formylphenyl) 4-dedimethylamino sancycline
[0480] 1730
[0481] 7-iodo-4-dedimethylamino sancycline (18A, 1 g, 1.5 3 mmol),
Pd(OAc).sub.2 (34 mg, 0.153 mmol), and MeOH (50 mL) are combined in
a 250 mL 2 neck round bottom flask equipped with a condenser and
argon line. The solution is then purged with argon (15 min) while
heated in an oil bath to approximately 70.degree. C. Sodium
carbonate (482 mg, 4.58 mmol) is dissolved in water (3-5 mL) and
added to reaction flask. The flask is then purged with argon for
another 5 minutes. 2-Methoxy-5-formylphenyl boronic acid (18B, 333
mg, 1.83 mmol) is dissolved in MeOH (5 mL) and added to reaction
flask. The flask is then purged again with argon for 10 minutes.
The reaction is monitored to completion within 3 hours. The
contents of the flask are filtered through filter paper and the
remaining solvent is evacuated. To make the hydrochloric acid salt,
the residue is dissolved in MeOH (sat. HCl). The solution is then
filtered and the solvent was evacuated. The product is then
characterized by .sup.1H NMR, LC-MS.
7-(2'-Methoxy-5'-N,N'-Dimethylaminomethylphenyl) 4-Dedimethylamino
Sancycline
[0482] 1731
[0483] The aldehyde (19A, 1 g, 1.82 mmol), dimethylamine HCl (19B,
297 mg, 3.64 mmol), triethylamine (506 .mu.L, 3.64 mmol), and
1,2-DCE (7 mL) are combined in a 40 mL vial. The contents are
dissolved within several minutes of shaking or stirring. Sodium
triacetoxyborohydride (772 mg, 3.64 mmol) is then added as a solid.
The reaction is monitored by HPLC and LC-MS and is complete within
3 hours. The reaction is quenched with MeOH (2 0 mL) and the
solvent is subsequently evacuated. The residue is redissolved in 3
mL DMF and separated on a C-18 column. Fractions from the prep
column dried down in-vacuo and the HCl salt are made by dissolving
contents in methanol (sat. HCl). The solvent is reduced and the
product is obtained and characterized by .sup.1H NMR, LC-MS,
HPLC.
EXAMPLE 2
Synthesis of 7,9-Substituted 4-Dedimethylamino Tetracycline
Compounds
7,9-Diiodo 4-dedimethylamino sancyline
[0484] 30.0 mL of concentrated sulfuric acid is added to 1.00 g of
4-dedimethylamino sancycline with stirring and the solution is then
cooled to 0.degree. C. 1.09 g of N-iodosuccinimide is added
portionwise to the solution over one hour and the reaction mixture
monitored by HPLC and TLC. The reaction mixture is poured into 250
mL of ice water, extracted three times with n-butanol, and the
solvent is removed under reduced pressure. The crude residue is
purified by preparative HPLC yielding 7-iodosancycline and
7,9-diiodosancycline.
7,9-Bis(3,4-Methylenedioxyphenyl)-Sancycline
[0485] 1732
[0486] 0.74 mmol of 7,9-diiodo 4-dedimethylamino sancycline (20C)
and 8.3 mg (0.37 mmol) palladium acetate are dissolved in 25 ml
methanol, under a nitrogen atmosphere. The solution is warmed to
60.degree. C. After stirring for ten minutes 234 mg (2.22 mmol),
sodium carbonate is added followed by 246 mg (1.48 mmol) of
3,4-methylenedioxyphenyl boronic acid (20B). After the reaction is
complete, the reaction mixture is filtered through a celite bed and
concentrated under reduced pressure. This crude product is purified
by preparative liquid chromatography using a C.sub.18 stationary
phase with eluent A: 0.1% TFA in water and eluent B: 0.1% TFA in
acetonitrile.
7 Iodo 4-Dedimethylamino Sancycline
[0487] One gram of 4-dedimethylamino sancycline is dissolved in 25
mL of TFA (trifluoroacetic acid) that was cooled to 0 C (on ice).
1.2 equivalents of N-iodosuccinimide (NIS) is added to the reaction
mixture and reacted for forty minutes. The reaction is removed from
the ice bath and is then allowed to react at room temperature for
an additional five hours. The mixture is then analyzed by HPLC and
TLC, driven to completion by the stepwise addition of NIS. After
completion of the reaction, the TFA is removed in vacuo and 3 mL of
MeOH is added to dissolve the residue. The methanolic solution is
then added slowly to a rapidly stirring solution of diethyl ether
to form a precipitate. The 7-iodo isomer of sancycline is purified
by treating the 7-iodo product with activated charcoal., filtering
through Celite, and subsequent removal of the solvent in vacuo to
produce the 7-isomer compound as a pure solid.
7-Tetramethylsilylethynyl-4-Dedimethylamino Sancycline
[0488] 1733
[0489] To a solution of 10 mmol of
7-iodo-4-dedimethylamino-sancycline trifluoroacetate 500 mg
tetrakis-triphenylphosphino-palladate, 500 mg copper(I) iodide, 100
mg palladium acetate and 30 ml triethylamine 3 ml
trimethylsilyl-acetylene is added. The reaction mixture is stirred
at room temperature for two hours than filtered through a celite
bed and concentrated. The dry material is picked up in methanol,
and the insolubles are filtered out. The solution is then
concentrated to recover the product (21B).
7-Ethynyl-4-Dedimethylamino Sancycline
[0490] 1734
[0491] 7-Tetramethylsilylethynyl-4-dedimethylamino-sancycline (21B)
is dissolved in 300 ml methanol, and stirred at 40.degree. C. with
6.8 g potassium carbonate. When no starting material is detected by
HPLC (.about.3 hours), the reaction mixture is cooled in an
ice/water bath and solids are removed by filtration. The structure
of the alkyne (22B) is confirmed by LCMS. 8B is then used without
further purification in the next step.
7-Ethyl-4-Dedimethylamino Sancycline
[0492] 1735
[0493] 10% palladium catalyst on charcoal (1 g) is added to
7-ethynyl 4-dedimethylamino sancycline (22B) in a saturated
methanol hydrochloric acid solvent. The mixture is placed in a
hydrogenator under 50 psi hydrogen pressure. After the reaction is
complete, the catalyst is filtered off, and the resulting solution
is concentrated. The crude product is purified by preparative
liquid chromatography using a C.sub.18 stationary phase with eluent
A: 0.1% TFA in water and eluent B: 0.1% TFA in acetonitrile. The
combined clean fractions are concentrated and hydrochloric acid
saturated isopropanol added. The pure product is precipitated by
addition of diethylether and filtered off.
7-Ethyl-9-Iodo-4-Dedimethylamino Sancycline
[0494] 1736
[0495] 7-Ethyl-4-dedimethylamino sancycline (23B, 6.7 mmol, 3.2 g)
is dissolved in 75 ml methanesulfonic acid at room temperature.
N-iodo succinimide (24B, 13.5 mmol, 3.05 g) is added over two hours
in 6 portions. After two hours diethyl ether is added, and the
precipitate is filtered off and dried. The crude product is
purified by preparative liquid chromatography using a C.sub.18
stationary phase with eluent A: 0.1% TFA in water and eluent B:
0.1% TFA in acetonitrile.
7-Ethyl-9-Cyclohexenylethynyl-4-Dedimethylamino Sancycline 1737
[0496] To a solution of 7-ethyl-4-dedimethylamino sancycline (1.13
mmol), 50 mg tetrakis-triphenylphosphino-palladate, 50 mg copper(I)
iodide, 10 mg palladium acetate and 3 ml triethylamine 0.1 ml
cyclohexenyl-acetylene was added. The reaction mixture is stirred
at 60.degree. C. for one hour, filtered through a celite bed and
concentrated. The dry material is dissolved in methanol and
filtered. The solution is then concentrated and purified using
preparative liquid chromatography. The preparative liquid
chromatography used a C.sub.18 stationary phase with eluent A: 0.1%
TFA in water and eluent B: 0.1% TFA in acetonitrile.
7-Iodo-9-t-Butyl-4-Dedimethylamino Sancycline
[0497] 1738
[0498] 9-t-butyl-4-dedimethylamino sancycline (26A, 1.13 g, 2 mmol)
is dissolved in 5 ml methanesulfonic acid (0.448, 2 mmol).
N-iodosuccinimide (26B) is added at room temperature over one hour
in four portions. The product (26C) is precipitated with diethyl
ether, filtered off and used in other reaction without further
purification.
7-(2-Methoxy-5-Dimethylaminomethylphenyl)-9-t-Butyl-4-Dedimethylamino
Sancycline
[0499] 1739
[0500] 7-Iodo-9-t-butyl-4-dedimethylamino sancycline (26B, 710 mg,
1.0 mmol) and palladium acetate (22.4 mg, 0.1 mmol) are dissolved
in 25 ml of methanol under a nitrogen atmosphere. Cesium carbonate
(3.25 g,10 mmol)and 2-methoxy-5-dimethylaminomethylphenyl-boronic
acid (27B, 0.435 g, 0.15 mmol) are added. The reaction mixture is
stirred at 60.degree. C. for two hours and then filtered through a
celite bed and concentrated under reduced pressure. The crude
product is purified by preparative liquid chromatography using a
C.sub.18 stationary phase with eluent A: 0.1% TFA in water and
eluent B: 0.1 % TFA in acetonitrile.
EXAMPLE 3
[0501] Preparation of 9-Substituted 4-Dedimethylamino Tetracycline
Compounds
Preparation of 9-Iodo 4-dedimethylamino minocycline
[0502] To 200 ml of 97% methanesulfonic acid is slowly added, at
ambient temperature, portionwise [56.56 mM] of 4-dedimethylamino
minocycline-hydrochloride salt. The dark solution is then stirred
at ambient temperature while [38 g; 1 69.7 mM] of N-iodosuccinimide
is added, in six equal portions, over 3.0 hours time. The reaction
is monitored via analytical LC, noting the disappearance of the
starting material. The reaction is slowly quenched into 2L of ice
cold water containing [17.88 g;1134.1 mM] of sodium thiosulfate
with rapid stirring. This quench is stirred for approximately 30
minutes at ambient temperature. The aqueous layer is then extracted
with 6.times.200 ml of ethyl acetate before the aqueous was poured
onto [259.8 g;3.08M] of sodium hydrogen carbonate containing 300 ml
of n-butanol. The phases are split and the aqueous extracted with
4.times.250 ml of n-butanol. The organic fractions are combined and
washed with 3.times.250 ml of water and once with 250 ml of
saturated brine. The resulting organic phase is reduced to dryness
under reduced pressure. The residue is suspended in methanol
(.about.600 ml) and anhydrous HCl gas is bubbled into this mixture
until solution occurred This solution is reduced to dryness under
reduced pressure. The filtrates are reduced to dryness under
reduced pressure. The resulting material is triturated with 300 ml
of methyl t-butyl ether and isolated via filtration. This material
is redissolved in 300 ml of methanol and treated with 0.5 g of wood
carbon, filtered and filtrates reduced to dryness under reduced
pressure. The material is again powdered under methyl t-butyl
ether, isolated via suction filtration and washed with more ether,
and finally hexanes. The material is vacuum dried to give the
product.
General Procedure For Preparation of 9-Alkynyl 4-Dedimethylamino
Minocycline Compounds
[0503] 1 mmol 9-iodo 4-dedimethylamino minocycline, 50 mg tetrakis
tripenylphosphinato palladate, 12 mg palladium acetate, 32 mg
copper (I) iodide are dissolved/suspended in 10 ml acetonitrile. 2
to 5 ml triethylamine and 3 to 5 mmol alkynyl 4-dedimethylamino
minocycline derivative is added. The reaction mixture is vigorously
stirred between ambient temperature to 70.degree. C. The reaction
time is 2-24 hours. When the reaction is completed the dark
suspension is filtered through a celite bed and concentrated. The
crude product is purified by prep HPLC. The combined fractions are
concentrated and taken up in .about.1 ml methanol. .about.3 ml HCl
saturated methanol is added, and the product is precipitated with
ether.
General Procedure For Preparation of 9-Aryl 4-Dedimethylamino
Minocycline Compounds
[0504] 0.15 mmol of 9-iodo 4-dedimethylamino minocycline, PdOAc
(3.2 mg), 229 .mu.l 2M Na.sub.2CO.sub.3 and 2 equivalents of phenyl
boronic acid are dissolved/suspended in 10 ml methanol. The
reaction flask is purged with argon and the reaction is run for a
minimum of four hours or until HPLC monitoring shows consumption of
starting material and/or the appearance of products. The suspension
is filtered through celite, and subject to purification by prep
HPLC on a divinylbenzene column.
9-(4-Trifluoromethoxyphenylureido)-Methyl Minocycline
[0505] 1740
[0506] To 3 mL of dimethylformamide is added 150 mg (0.25 mmol) of
9-methyl amino 4-dedimethylamino minocyline trihydrochloride and 67
mL (0.50 mmol) of triethylamine at 25.degree. C. With stirring, 75
mL (0.50 mmol) of 4-trifluoromethoxyphenylisocyanate is added and
the resulting reaction mixture is stirred at 25.degree. C. for two
hours. The reaction is monitored by analytical HPLC (4.6.times.50
mm reversed phase Luna C18 column, 5 minute linear gradient 1-100%
B buffer, A buffer is water with 0.1% trifluoroacetic acid, B
buffer is acetonitrile with 0.1% trifluoroacetic acid). Upon
completion, the reaction is quenched with 1 mL of water and the pH
adjusted to approximately 2.0 with concentrated HCl. The solution
is filtered and the compound purified by preparative HPLC.
9-(4'Carboxy phenyl) 4-Dedimethylamino Minocycline
[0507] 1741
[0508] In a clean, dry reaction vessel, is placed 9-iodo
4-dedimethylamino minocycline [0.762 mmoles]bis HCl salt, palladium
(II) acetate [17.2 mg; 0.076 mmoles] along with 10 ml of reagent
grade methanol. The solution is immediately purged, with stirring,
with a stream of argon gas for approximately 5 minutes. The
reaction vessel is brought to reflux and to it is sequentially
added via syringe 2M potassium carbonate solution [1.91 ml; 3.81
mmoles], followed by a solution of p-carboxyphenyl boronic acid
[238.3 mg; 1.53 mmoles]in 5 ml of reagent DMF. Both of these
solutions are previously degassed with argon gas for approximately
5 minutes. The reaction is heated for 45 minutes, the progress is
monitored via reverse phase HPLC. The reaction is suctioned
filtered through a pad of diatomaceous earth and the pad is washed
with DMF. The filtrates are reduced to an oil under vacuum and
residue is treated with t-butylmethyl ether. Crude material is
purified via reverse phase HPLC on DVB utilizing a gradient of
water and methanol/acetonitrile containing 1.0% trifluoroacetic
acid.
EXAMPLE 4
Synthesis of 13- Substituted 4-Dedimethylamino Methacycline
Compounds
General Procedure for Phenyl Boronic Acid Derivitization of
4-Dedimethylamino methacycline
[0509] 4-Dedimethylamino methacycline (1 equiv.), PdCl.sub.2 (0.14
equiv.), and CuCl.sub.2 (0.90 equiv.) are dissolved in 20 ml of
MeOH and heated under nitrogen atmosphere. After 1 hour, the
boronic acid (2 equiv.) is added and the reaction mixture is heated
for another 6-10 hours. The reactions are monitored by TLC or
analytical HPLC. The reaction mixture is then cooled to room
temperature and passed through a bed of celite. Evaporation of the
solvent generally gives a yellow-brown solid, which is purified
using preparative HPLC (CH.sub.3CN:MeOH:H.sub.2O- ). The solvent is
then evaporated from the product giving a yellow solid, which is
then dissolved in MeOH and purged with HCl gas. After evaporation
of MeOH, the yellow material is dried under vacuum for several
hours.
Synthesis of 5-propionyl-13-(4'-chlorophenyl) 4-dedimethylamino
methacycline
[0510] 500 mg of 13-(4'-Cl phenyl) 4-dedimethylamino methacycline
is dissolved in 20 ml of anhydrous HF. 3 ml of propionic acid is
added and the reaction left for 2 days at room temperature. The HF
is removed under a steady stream of N.sub.2, and the residue is
triturated with Et.sub.2O to yield a dark yellow solid. The solid
is dissolved in MeOH, and chromatographed on a divinyl benzene
resin using an acetonitrile gradient from 30% to 100% with a
primary solvent system of 0.1% formic acid. The corresponding
fractions are collected and dried in vacuo to yield the product.
The yellow solid is dissolved in MeOH and HCl gas is bubbled in to
produce the product as a yellow solid HCl salt.
Synthesis of 9,13-di-t-butyl 4-Dedimethylamino Methacycline
[0511] 1.0 g of 4-dedimethylamino methacycline is added to 15 ml of
concentrated H.sub.2SO.sub.4. 5 ml of isobutylene or t-butanol is
added and the reaction is stirred for 6 hours at room temperature.
The reaction is neutralized with Na.sub.2CO.sub.3 (8 grams) and 40
ml of water, and the aqueous layer is extracted 3.times. with 100
ml of N-butanol. The extracts are combined and dried to yield 69%
of product as a light yellow solid. An analytical sample is
obtained by the chromatography on divinyl benzene using a gradient
of acetonitrile from 30-100% over 30 minutes against a primary
solvent of 0.1% formic acid.
EXAMPLE 5
Synthesis of 8-Substituted 4-Dedimethylamino Tetracycline
Compounds
9-NO.sub.2 4-Dedimethylamino Doxycycline
[0512] 1.0 g of 4-dedimethylamino doxycycline HCl is dissolved in
concentrated H.sub.2SO.sub.4 (5 ml) and NaNO.sub.3 (1.1 eq) is
added over 1 minute. The reaction is stirred for 1 hour and
subsequently dripped into cold, rapidly stirred ether (500 ml). The
precipitate is washed with ether and dried in vacuum to yield
9-NO.sub.2 4-dedimethylamino doxycycline without further
purification.
9-NH.sub.2 4-Dedimethylamino Doxycycline
[0513] 9-NO.sub.2 4-dedimethylamino doxycycline (1 g) is dissolved
in methanol (50 ml) and poured into a Parr apparatus with 100 mg of
10% Pd/C. The reaction is charged with H.sub.2 and shaken for 2
hours. The 9-amino 4-dedimethylamino doxycycline is separated by
preparative apic purification to produce 9-NH.sub.2
4-dedimethylamino doxycycline and 7-NH.sub.2 4-dedimethylamino
doxycycline.
9-N.sub.2 4-Dedimethylamino Doxycycline
[0514] 9-NH.sub.2 4-dedimethylamino doxycycline (1.5 g) is
dissolved in 50 ml of 0.1N methanol HCl and 2.2 ml of butyl nitrate
is subsequently added. The reaction is stirred for 1 hour, then the
product is precipitated in 400 mL of dry ether to produce the
9-diazonium salt of 4-dedimethylamino doxycycline
9-Azido 4-Dedimethylamino Doxycycline
[0515] Sodium azide (0.126 g) is added to a warm 0.1 N methanol/HCl
solution of the 9-diazonium salt (1 g). The mixture is then stirred
at room temperature for 4 hours and the product is obtained by
precipitation into diethyl ether.
9-NH.sub.2-8-Bromo 4-Dedimethylamino Doxycycline
[0516] 0.5 g of 9-azido 4-dedimethylamino doxycycline is added to
10 mL of HBr in acetic acid (30 wt %) and the reaction is stirred
at room temperature for 1 hour. The product is obtained by
preparative C18 HPLC.
8-Bromo 4-Dedimethylamino Doxycycline
[0517] 100 mg of 9-amino-8-bromo 4-dedimethylamino doxycycline is
reacted with 1.1 g of butyl nitrate in 0.1N HCl to produce the
9-diazonium salt of the 8-bromo 4-dedimethylamino doxycycline. The
reaction is treated with phosphoric acid to yield the product as
crude solid. Preparative HPLC is used to purify the product.
8-Phenyl-4-Dedimethylamino Doxycycline
[0518] 8-bromo 4-dedimethylamino doxycycline, 150 mg, Pd(OAc).sub.2
and 10 mL of MeOH are added to a flask with a stir bar and the
system degassed three times using argon. Na.sub.2CO.sub.3 (87 mg,
0.8 mM) dissolved in water and argon degassed is added via syringe
and is added along with phenylboronic acid (68 mg, 0.55 mM) in MeOH
that was also degassed. The reaction is followed by HPLC for 2
hours and then the reaction mixture is cooled to room temperature.
The solution is filtered, and dried to produce a crude mixture. The
solid is dissolved in dimethylformamide and injected onto a
preparative HPLC system using C18 reverse-phase silica. The product
fraction is isolated, and the solvent is removed in vacuo to yield
the product.
8-Ethynyl-4-Dedimethylamino Doxycycline
[0519] 1 mmol 8-bromo 4-dedimethylamino doxycycline, 50 mg tetrakis
tripenylphosphinato palladate, 12 mg palladium acetate, 32 mg
copper (I) iodide are dissolved/suspended in 10 ml acetonitrile. 2
to 5 ml triethylamine and 3 to 5 mmol ethyne is added. The reaction
mixture is vigorously stirred between ambient temperature to
70.degree. C. The reaction time is 2-24 hours. When the reaction is
completed the suspension is filtered through a celite bed and
concentrated. The crude product is purified by prep HPLC. The
combined fractions are concentrated and taken up in 1 ml methanol.
.about.3 ml HCl saturated methanol is added, and the product is
precipitated with ether.
8-Ethenyl-4-Dedimethylamino Doxycycline
[0520] 1 mmol 8-bromo 4-dedimethylamino doxycycline, 50 mg tetrakis
tripenylphosphinato palladate, 12 mg palladium acetate, 32 mg
copper (I) iodide are dissolved/suspended in 10 ml acetonitrile. 2
to 5 ml triethylamine and 3 to 5 mmol ethene is added. The reaction
mixture is vigorously stirred between ambient temperature to
70.degree. C. The reaction time is 2-24 hours. When the reaction is
completed the suspension is filtered through a celite bed and
concentrated. The crude product is purified by prep HPLC. The
combined fractions are concentrated and taken up in .about.1 ml
methanol. .about.3 ml HCl saturated methanol is added, and the
product is precipitated with ether.
EXAMPLE 6
In vitro Minimum Inhibitory Concentration (MIC) Assay
[0521] The following assay is used to determine the efficacy of the
tetracycline compounds against common bacteria. 2 mg of each
compound is dissolved in 100 .mu.l of DMSO. The solution is then
added to cation-adjusted Mueller Hinton broth (CAMHB), which
results in a final compound concentration of 200 .mu.g per ml. The
tetracycline compound solutions are diluted to 50 .mu.L volumes,
with a test compound concentration of 0.098 .mu.g/ml. Optical
density (OD) determinations are made from fresh log-phase broth
cultures of the test strains. Dilutions are made to achieve a final
cell density of 1.times.10.sup.6 CFU/ml. At OD=1, cell densities
for different genera should be approximately:
4 E. coli 1 .times. 10.sup.9 CFU/ml S. aureus 5 .times. 10.sup.8
CFU/ml Enterococcus sp. 2.5 .times. 10.sup.9 CFU/ml
[0522] 50 .mu.l of the cell suspensions are added to each well of
microtiter plates. The final cell density should be approximately
5.times.10 CFU/ml. These plates are incubated at 35.degree. C. in
an ambient air incubator for approximately 18 hr. The plates are
read with a microplate reader and are visually inspected when
necessary. The MIC is defined as the lowest concentration of the
tetracycline compound that inhibits growth.
Equivalents
[0523] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of the present
invention and are covered by the following claims. The contents of
all references, patents, and patent applications cited throughout
this application are hereby incorporated by reference. The
appropriate components, processes, and methods of those patents,
applications and other documents may be selected for the present
invention and embodiments thereof.
[0524] This application is related to U.S. patent application Ser.
No. 09/895,812, entitled "7-Substituted Tetracycline Compounds,"
filed Jun. 29, 2001; U.S. Provisional Patent Application Serial No.
60/275,576, entitled "7-Substituted Tetracycline Compounds" filed
Mar. 13, 2001, and U.S. Provisional Patent Application Serial No.
60/216,760, entitled "7-Substituted Sancycline Compounds" filed on
Jul. 7, 2000; the entire contents of each of these applications are
hereby incorporated herein by reference.
[0525] This application is also related to U.S. patent application
Ser. No. 09/895,797, entitled "7, 9- Substituted Tetracycline
Compounds," filed on Jun. 29, 2001; and U.S. Provisional Patent
Application Serial No. 60/275,620, entitled "7,9-Substituted
Tetracycline Compounds," filed on Mar. 13, 2001. The entire
contents of each of these applications are hereby incorporated
herein by reference.
[0526] This application is also related to U.S. patent application
Ser. No. 09/895,857, entitled "9-Substituted Minocycline
Compounds," filed on Jun. 29, 2001; U.S. Provisional Patent
Application Serial No. 60/275,621, entitled "9-Substituted
Minocycline Compounds," filed on Mar. 13, 2001, and U.S.
Provisional Patent Application Serial No. 60/216,659, entitled
"9-Substituted Minocycline Compounds," filed on Jul. 7, 2000, the
entire contents of each of which are incorporated herein by
reference.
[0527] This application is also related to U.S. patent application
Ser. No. 09/895,796, filed on Jun. 29, 2001; U.S. Provisional
Application Serial No. 60/216,580, filed on Jul. 7, 2000; U.S.
Provisional Application No. 60/154,701, filed on Sep. 14, 1999;
U.S. Provisional Application No. 60/193,972, filed on Mar. 31,
2000; U.S. Provisional Application No. 60/193,879, filed on Mar.
31, 2000; U.S. Provisional Application No. 60/204,158, filed on May
15, 2000; U.S. Provisional Application No. 60/212,030, filed Jun.
16, 2000; and U.S. Provisional Application No. 60/212,471, filed
Jun. 16, 2000, the entire contents of each of these applications
are hereby incorporated herein by reference.
[0528] This application is related to U.S. patent application Ser.
No. 09/894,805, entitled "7, 8, and 9 Substituted Tetracycline
Compounds," filed on Jun. 29, 2001; U.S. Provisional Patent
Application Serial No.: 60/216,656, entitled "7, 8 and
9-Substituted Tetracycline Compounds," filed on Jul. 7, 2000; and
International Patent Application Serial No.: PCT/US00/21366,
entitled, "8-Substituted Tetracycline Compounds," filed on Aug. 4,
2000. The application is also related to U.S. Ser. No. 60/395,696,
filed Jul. 12, 2002. The entire contents of each of these
applications are hereby incorporated herein by reference.
* * * * *